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Several treatment options have been explored for rhinoviral infections throughout the years. Capsid binders, capable of inhibiting viral entry, were considered to be promising agents, showing solid antiviral activity in vitro. A randomized trial, however, showed limited clinical benefit of intranasal pirodavir for naturally occurring rhinovirus colds; it did, however, reduce viral shedding on Days 3 and 7, a benefit which may be of interest for patients with underlying haematological malignancies. Likewise, pleconaril, whether in oral or intranasal formulations, proved to only provide a modest clinical benefit, reducing the duration of symptoms in otherwise healthy adults with rhinoviral cold within 1 to 1.5 days; it has also been proven to be potentially beneficial in neonates with severe enterovirus infection, warranting further research. Oral vapendavir, a newer capsid binder, recently failed to prove superior to placebo in improving lung function or reducing asthma exacerbations in asthmatic patients; it did, however, result in a statistically significant antiviral effect (demonstrated by a negative RV PCR) when administered within 24 h of symptom onset (NCT02367313). Based on this finding, a phase 2 trial studying vapendavir treatment for HSCT patients with RV URTI was planned (NCT03024177), but was later withdrawn. Other classes of antiviral agents, including the 3C protease inhibitor rupintrivir, the nucleoside analog inhibitor MK-0608, and the phosphatidylinositol 4-kinase IIIβ (PI4K-IIIβ) kinase inhibitor PIK93, were shown to exhibit in vitro activity against Rhinovirus type C in a comprehensive study utilizing subgenomic-replicon- and infectious-virus-replication-based assays. While clinical benefit for any of these agents has yet to be demonstrated, HSCT recipients/candidates would certainly stand to gain much from the judicious implementation of one such treatment option.
Regardless of treatment options, the ease with which respiratory viruses are transmitted makes the enforcement of infection control measures critical to reducing the spread of these infections, and doubly important in at-risk population groups. Nosocomial transmission is also common, often with devastating consequences, making the need for adequate prevention all the more stringent. In addition, deferral of HSCT has been shown to reduce the risk of progression to pneumonia.
One possible general antiviral agent investigated in uncontrolled trials has been aerosolized and/or systemic ribavirin, with or without intravenous immunoglobulin association. This has been proven to be safe to administer and appears to be effective in both preventing progression to LRTI and treatment of pneumonia caused by RSV and HPIV, although more randomized trials are needed to confirm this. Concerns exist about the limitations of aerosolized ribavirin in regards to environmental exposure and potentially teratogenic effects in pregnant healthcare workers and visitors, special air-flow requirements, and high cost, making intravenous and oral administration viable alternatives.
Palivizumab, a monoclonal antibody targeting RSV protein F, has also emerged as a potentially effective agent, particularly in the prophylaxis of RSV pneumonia in both children and adults at increased risk of severe disease, but also in treatment of persistent RSV infection in children with leukemia and improving outcomes in children with RSV LRTID.
Investigations of novel agents have been met with mixed results. ALS-008176 (lumicitabine), an oral nucleoside analogue prodrug with promising preliminary results, started several phase 2 trials studying its efficacy on RSV infections in children and infants (NCT03333317, NCT03332459), as well as one study following its effect on hospitalized adults with metapneumovirus infection (NCT03502694); these trials have, however, been suspended by the sponsor. GS-5806 (presatovir), a drug blocking RSV fusion protein, has undergone several trials, studying its effects on both general population (NCT02135614) and HSCT recipients with RSV URTI (NCT02254408) and LRTI (NCT02254421); results have not yet been published. AK0529 (ziresovir), an orally bioavailable RSV fusion protein inhibitor, is currently undergoing a phase 2 study on adults with RSV infection in China (NCT03699202), while a multicentric study on a pediatric population has been completed, with results upcoming (NCT02654171). ALX-0171, a trimeric nanobody that binds to the antigenic site II of the RSV F protein with high affinity, has proven superior in vitro neutralization to that of palivizumab.. Several other agents, including L-protein and N-protein inhibitors, the full description of which is beyond the scope of this review, are currently under study and have been described elsewhere.
Pneumococcus is an important pathogen in childhood [1–3]. Invasive pneumococcal disease refers to unlocalised bacteremia, pneumonia, or meningitis. Despite the availability of effective vaccines, new serotypes continue to evolve [1–3]. The Hong Kong Government introduced the 7-valent polysaccharide vaccine in September 2009. In 2010, the vaccine was changed to the 10-valent vaccine and in 2011 recommendation was made to switch to a 13-valent vaccine. Locally, the coverage of the 7-valent or 10-valent and 13-valent vaccines was 65% and 90%, respectively. The parents reported that the child received one prior dose of 7-valent vaccine before 3 years of age in early 2010. It is possible that 19A was a commonly circulating strain before the introduction of the 10-valent or 13-valent vaccines. The 13-valent vaccine should stop circulation of 19A when the program is fully implemented.
History of immunization with the 7-valent vaccine is not a guaranteed prevention against pneumococcal infection in children [1–3]. Evolving serotypes associated with severe lobar pneumonia, pleural effusion, and PICU admission despite prior immunization have been previously reported locally.
Evidenced-based guidelines for management of infants and children with community-acquired pneumonia (CAP) were prepared by an expert panel comprising clinicians and investigators representing community pediatrics, public health, and the pediatric specialties of critical care, emergency medicine, hospital medicine, infectious diseases, pulmonology, and surgery. Amoxicillin should be used as first-line therapy for previously healthy, appropriately immunized infants and preschool-aged children with mild to moderate CAP suspected to be of bacterial origin. Amoxicillin provides appropriate coverage for S. pneumoniae, the most prominent invasive bacterial pathogen. Macrolide antibiotics should be prescribed for treatment of children (primarily school-aged children and adolescents) evaluated in an outpatient setting with findings compatible with CAP caused by atypical pathogens. Laboratory testing for M. pneumoniae should be performed if available in a clinically relevant time frame. Ampicillin or penicillin G should be administered to the fully immunized infant or school-aged child admitted to a hospital ward with CAP when local epidemiologic data document lack of substantial high-level penicillin resistance for invasive S. pneumoniae. Empiric therapy with a third-generation parenteral cephalosporin (ceftriaxone or cefotaxime) should be prescribed for hospitalized infants and children who are not fully immunized, in regions where local epidemiology of invasive pneumococcal strains documents high-level penicillin resistance, or for infants and children with life-threatening infection, including empyema. Empiric combination therapy with a macrolide (oral or parenteral), in addition to a beta-lactam antibiotic, should be prescribed for the hospitalized child for whom M. pneumonia and C. pneumoniae are significant considerations; diagnostic testing should be performed if available in a clinically relevant time frame. Accordingly, earlier initiation of antibiotics might have increased the chances of survival in this child.
Antibiotic resistance has also developed in Hong Kong [1, 2]. The serotype 19A is especially virulent and may be difficult to isolate in patients who have already been started on antibiotics. The pathogen has been reported to be associated with the hemolytic uremic syndrome [6–11]. Penicillin can be used in sensitive pneumococcus [1, 2]. In patient with pneumonia not responding satisfactory initially, more invasive investigative/therapeutic management including a pleural drain for biologic specimen is indicated to guide management. Local antimicrobial sensitivity in PICU patients has been reported [1, 2]. The pathogen was sensitive to penicillin and cefotaxime in this case. In patients not responding satisfactorily with initial antibiotics but with known penicillin sensitivity, a higher dose of penicillin should be tried.
Coinfections by viral and bacterial agents in critically ill patients have been reported [12–15]. Mycoplasma pneumoniae usually affects older children and a clinical entity of atypical pneumonia or “walking” pneumonia. Metapneumovirus usually causes co-infection. Occasionally, both pathogens can cause severe acute respiratory symptoms just like SARS (severe acute respiratory syndrome).
In-house real-time RT-PCRs were performed according to hospital laboratory standard operating procedures for the qualitative detection of human Metapneumovirus (hMPV) RNA and of Mycoplasma pneumoniae (MP). The target of amplification for hMPV was the nucleoprotein gene (N gene) with primer sequences and method as described by Hopkins et al. and 45 cycles were run on real-time PCR (ABI prism 7900 HT FAST). Positive and negative controls were included, and a Ct value of ≤37 was considered positive. The target of amplification for MP was the ADP-ribosylating toxin gene encoding the CARDS (community-acquired respiratory distress syndrome) toxin using primer pairs and method as described by Winchell et al.. Both internal DNA control and a positive and negative control were included in the reaction run. A Ct value ≤34 was considered positive.
It is difficult to ascertain if Metapneumovirus and Mycoplasma had contributed to this fatal illness. These pathogens were detected in the tracheal and the nasopharyngeal aspirates but not in the postmortem lung tissue cultures. Unlike the nasopharynx, the presence of any pathogens in the tracheal aspirates represents infection in the lower respiratory tract rather than carriage in the upper airway. Both pathogens are known to cause pneumonia on their own and both are not commonly carried by healthy young persons [5, 13, 19–22]. These facts support the argument that they were copathogens with pneumococcus which was found in pleural fluid, tracheal aspirates, and blood. In conclusion, the simultaneous isolations of 3 respiratory viral and bacterial pathogens have not been reported in our locality and may contribute to the fatal outcome of this unfortunate child.
The pre-publication history for this paper can be accessed here:
The treatment and clinical outcomes between the severe and non-severe groups are compared in Table3. There were no significant differences in antimicrobial therapy, intensive care units, hemodialysis, and mechanical ventilation between the two groups. All patients from the two groups received the appropriate antibiotic therapy for pneumococcal pneumonia based on the antimicrobial susceptibility results. Twenty-three (12·0%) patients received antibiotics for pneumococcal pneumonia prior to arriving at this hospital, which was not significantly different between the case and the control groups (14 [14·1%] vs. 9 [9·8%], respectively; P = 0·355). The resistance rates of the pneumococcal isolates to penicillin and levofloxacin were significantly higher in the case group than in the control group (Table4).
The all-cause in-hospital mortality rate and pneumonia-related mortality rate were 8·4% and 6·3%, respectively. The median length of hospital stay for inpatients was 8 days (IQR, 4–18). Patients with severe pneumococcal pneumonia showed higher pneumonia-related mortality and longer hospital stays than patients with non-severe pneumococcal pneumonia (Table3).
Leukotriene receptor antagonist was prescribed in asthmatic patients with or without ICS. Montelukast treatment did not improve asthma control or cold symptom scores when HRV were experimentally inoculated into mild asthmatics, or healthy subjects (Kloepfer et al., 2011). It is uncertain whether leukotriene receptor antagonist treatment is effective in the reduction of asthma symptoms associated with HRV infection.
Inhaled corticosteroid (ICS) is the main drug for regular asthma therapy. ICS treatment improved airway hyperresponsiveness in asthmatic patients experimentally challenged with HRV, however, ICS treatment did not reduce accumulation of inflammatory cells, except for eosinophils in bronchial epithelium (Grunberg et al., 2001). Double-stranded RNA (dsRNA), a viral product and a ligand for the Toll-like receptor-3 (TLR3), upregulates the expression of inflammatory chemokines in airway epithelial cells. Matsukura et al. (2013) reported that treatment of BEAS-2B cells with fluticasone propionate significantly and dose-dependently inhibited dsRNA-induced expression of CCL5, CXCL8, and CXCL10 protein and mRNA. To confirm the effect on ssRNA, such as that of HRV, would need further studies.
In conclusion, preceding or concurrent RVIs might significantly influence the clinical severity in patients with pneumococcal pneumonia in addition to other factors, such as male sex, old age, hypoalbuminemia, and azotemia. Further studies are needed to understand the role of preceding or concurrent RVIs and to determine the clinical benefits of routine viral diagnostic tests for RVIs in patients with pneumococcal pneumonia.
Our study demonstrated that viruses were identified in the oropharynx of 22.2% and bacterial infections were confirmed in 41.7% of the patients with COPD exacerbations requiring ED visits. The most commonly identified virus was PIV3, and the most commonly found bacterium was H. influenzae. Higher percentages of the virus-positive patients presented with sore throat and with the family cluster of common cold symptoms. The analysis of maintenance medications prescribed before the ED visits showed that the percentage of patients who had oral corticosteroid treatment prior to the ED admission was higher in the virus-positive group. Multivariate analysis for evaluation of the risk factors for recurrent exacerbations showed a higher rate of recurrent COPD exacerbation in the 1-year period after the original ED visit in those with an increased sputum volume during the first COPD exacerbation. However, the commonly used biomarkers for infection, such as serum CRP or PCT levels, did not aid in differentiating between bacterial or viral infections in patients with COPD exacerbations.
A more rapid decline of lung function is observed in COPD patients with exacerbations.17 The patients with exacerbations also had higher mortality rates and more frequent exacerbations requiring hospital admissions.18 Papi et al found that infective exacerbations were detected in 78% of patients, with bacteria identified in 54.7% and viruses in 48.4%.4 COPD exacerbations in which pathogens were identified were associated with longer hospitalization stays than noninfective exacerbations.4 However, the positive rates of viral identification in patients with COPD exacerbations requiring hospitalization varied in different publications. In the study by Kherad et al in which the samples for virus identification were obtained via nasopharyngeal swabs and the identification was performed using qualitative RT-PCR assays, the overall virus-positive rate was 51%.19 McManus et al showed that 36.8% of patients hospitalized for COPD exacerbations had sputum samples that were positive for viruses.20 In a study of patients with COPD exacerbations requiring mechanical ventilation, viruses were identified in 43% of nasopharyngeal aspirates and posterior pharyngeal swabs.21 In our study, viral pathogens were detected in the oropharyngeal swabs of 16 patients (22.2%). The virus-positive rate of the oropharyngeal swabs was thus lower than in the previous studies. The possible causes of the variation may include seasonal and geographic differences in the etiology of virus-associated COPD exacerbations. In a recent systematic review, the rates of detection of viruses associated with COPD exacerbations were highest in Europe.7 Another possible cause of the differences in the results is the site of the sample collections. In our study, we collected oropharyngeal swabs but not nasopharyngeal swabs or sputum samples, which might result in different rates of viral detection.
In this study, the commonly identified viruses in patients with COPD exacerbations requiring ED visits were PIV3, Inf A virus, and human rhinovirus. This result was similar to the finding of Cameron et al from a study in Australia in which the most frequently detected viral etiologies were Inf A, PIV3, and rhinovirus.21 In a recent review of eight studies, picornavirus was the most common virus in western countries and influenza virus was most common in Asia.7
H. influenzae was the most common bacterial pathogen in COPD exacerbations in a previous study.4
Pseudomonas aeruginosa and Klebsiella pneumoniae were also emphasized in recent studies.22,23 In our study, H. influenzae, H. parainfluenzae, and K. pneumoniae were the most commonly identified bacteria. Our data provided worthwhile epidemiologic results of viral and bacterial etiologies of COPD exacerbation, and this may have important implications for appropriate empirical selection of antibiotics and proper management of COPD exacerbations.
Biomarkers are commonly used to differentiate infective or noninfective causes of COPD exacerbations. We compared WBC, CRP, and PCT levels between the bacteria-positive and bacteria-negative patients, and these biomarkers did not show statistically significant between-group differences in our study. Similarly, for the WBC, CRP, and PCT levels, the differences between the virus-positive and virus-negative patients were not statistically significant. PCT is a biomarker that is more specific for bacterial infection and might be useful as a guide for decisions regarding antibiotic treatment. However, it could not distinguish bacterial from viral and noninfectious causes of COPD exacerbations.13 Daniels et al compared CRP and PCT as markers of clinical outcome in COPD exacerbations and found that PCT was not a good biomarker in COPD exacerbations because patients with low PCT values did benefit from antibiotics.24 The severity of the bacterial infections of the airways in some patients with COPD exacerbations is probably insufficient to induce a significant PCT production.
Sputum purulence has been suggested to be useful in determining the initiation of antibiotic treatment in hospitalized patients with COPD exacerbations.25 However, there was no difference in sputum purulence between the bacteria-positive and bacteria-negative groups in our study. In a retrospective cohort study, up to 85% of patients hospitalized for COPD exacerbations were treated with antibiotics.26 Although the GOLD guidelines suggest “the use of antibiotics in exacerbations remains controversial” and “consider antibiotic when signs of bacterial infection”, the study by Rothberg et al supported antibiotic administration as improving the outcomes among patients hospitalized for COPD exacerbations.27
COPD exacerbation patients in whom oropharyngeal viruses were identified were more likely to have had previous corticosteroid treatment, a sore throat, and a family cluster of common cold symptoms. Clinicians should consider virus-induced COPD exacerbations if the patients present with a sore throat or a family cluster of common cold symptoms.
A total of 52% of our patients had recurrent exacerbations during the subsequent 1-year period after the exacerbation. Hurst et al reported on a cohort of patients with COPD and showed that 39% of patients with stage 2, 52% with stage 3, and 62% with stage 4 COPD had exacerbations during the preceding year.28 Bafadhel et al divided COPD exacerbations to four distinct clusters, including bacterial, viral, eosinophilic predominant, and pauci-inflammatory, by biomarkers such as sputum IL-1β or serum CXCL10.29 We analyzed the clinical variables associated with the 1-year recurrent exacerbation rate, and increased sputum volume during the initial COPD exacerbation was the only independent risk factor for recurrent exacerbations in the subsequent 1-year period. Our study provides additional information for further investigation about COPD phenotypes of recurrent exacerbations.
There are some limitations in this study, which should be mentioned. First, the techniques used in this study cannot distinguish acute infection from colonization. Therefore, we selected patients requiring ED visits rather than only symptom-based exacerbations. Second, although this study was conducted in a 3,300-bed tertiary teaching hospital, it was still a single-center, not a multicenter, study, and our results were obtained for a very low number of patients. Third, whether these patients had prior influenza or pneumococcal vaccinations had not been recorded. We could not clarify the influence of vaccinations in COPD exacerbations from this study. Further, virus was assessed both by cultures and by PCR, but bacteria were identified only by culture. Finally, our virus identification was obtained from oropharyngeal swab specimens. We did not obtain specimens from nasopharyngeal swabs or the lower respiratory tract for virus identification. The actual rates of virus identification in different sampling sites were unknown.
In conclusion, viruses and bacteria both play important roles in COPD exacerbations. WBC, PCT, and CRP levels are not good indicators for bacterial infections in COPD exacerbations. Those with increased sputum volume in COPD exacerbation had a higher rate of recurrent exacerbations in the subsequent 1-year period. Understanding the etiologies of bacteria and viruses in COPD exacerbations might aid in the appropriate management of COPD exacerbations.
The recent asthma studies demonstrated the relationship between viral infections and the development of asthma [1, 2]. Even in the recent guidelines, there is few description of the association between bacterial infection and asthma [1–3]. In this study, infection with S. pneumoniae was the risk factor for adult asthma exacerbation in clinical practice.
The current guideline was developed using an evidence-based medicine analysis, which utilized several clinical studies. Patients with a heavy smoking history or comorbid COPD or pneumonia were usually excluded in almost all of the clinical asthma studies. However, many asthmatic inpatients have a history of heavy smoking and some have comorbid COPD or pneumonia in clinical practice. The results of the present study are useful for many practicing clinicians because the patients in the present study were not all non-smoking uncomplicated asthmatics.
It was found that viral infection, especially with IF, RSV, and HRV, was important for asthma exacerbation. These results are consistent with previous reports [5–7, 14]. Surprisingly, viruses were detected by multiplex PCR analysis in half of the stable asthmatic outpatients, indicating that several viruses were the common human respiratory microbes. Compared to stable asthmatic outpatients, higher incidences of HRV, RSV, and metapneumovirus infections were observed in asthma exacerbation inpatients, indicating that viral infection, especially with HRV, RSV, or metapneumovirus, plays an important role in adult asthma exacerbation in clinical practice. Prevention of infections with these viruses is important for decreasing asthma exacerbations in clinical practice. The relationship between viral infection and asthma exacerbation may be explained by TLR or ICAM-1 [20, 21, 23–27], but a higher incidence of smoking may affect viral infection in asthmatic patients in clinical practice.
Bacterial infection has not been the focus of previous studies of asthma exacerbation because patients who smoked or had COPD were usually completely excluded in usual clinical asthma studies. In the present study, there was a relationship between bacterial infection and asthma exacerbation in clinical practice. Considering the results of this practical, clinical study, comorbid sinusitis may be the most important factor related to susceptibility to bacterial infection in asthmatic patients. The presence of comorbid pneumonia may also affect the susceptibility of asthmatic patients to bacterial infection. Although S. pneumoniae, H. influenzae, and M. catarrhalis are the major bacterial infections in the respiratory tract, only H. influenzae was detected from stable asthmatic outpatients. These results indicate that bacteria other than H. influenzae contributed to asthma exacerbation in clinical practice. Early treatment with antibiotics, as well as steroid and bronchodilators, may be required for treatment of asthma exacerbation in these patients. It is important for clinicians to detect and treat bacterial infections in patients with asthma exacerbation in clinical practice. In the view point of the prevention of bacterial infection, pneumococcal vaccination is most important for asthmatic patients.
Co-infections with virus and bacteria were observed in 18.8% of asthma attack patients in this study. Wark et al. reported that the viral and bacterial co-infections increased the risk of readmission in asthmatic and COPD patients. This is an important issue when taking care of these asthmatic patients.
The exacerbation group had a higher number of smokers versus the stable asthmatics in our study. The mechanism of this result may be explained by steroid resistance (via the histone deacetylase 2 pathway or overexpression of glucocorticoid receptor β) in severe smoking asthma. [29, 30]
There are some limitations in this study. Although 98% of asthma exacerbation inpatients had a history of a common cold before their asthma attack, a pathogen was detected from nasopharyngeal swabs in only 70% of patients. Overall, 15 major viruses and 6 major bacteria were evaluated by multiplex PCR analysis. It is possible that other minor pathogens may be involved in asthma exacerbations in clinical practice. Another possible reason for the low yield is inappropriate timing of the taking of nasal swabs. The pathogen causing the common cold may have disappeared at the time the nasal swab was taken in some patients. Another reason is that some patients may have only had a lower respiratory tract infection. The symptom from the patients with allergic rhinitis may be misinterpreted as being due to a respiratory infection. Furthermore, this study is not a result from longitudinal data. We checked the microbes only once on admission. If we check the microbes several times, we can clearly elucidate whether the detected microbe is infection or colonization. Several pathogens were different between stable outpatients and asthma exacerbation inpatients. However, only the detection rate of S. pneumoniae was statisitically significant because the number of stable outpatients was too small compared to asthma exacerbation inpatients. If we could get the larger number of outpatients, other pathogen may be related to asthma exacerbation.
In conclusion, several viral and bacterial infections were observed in patients with asthma attacks in clinical practice. Infection with S. pneumoniae was related to adult asthma exacerbation. In the future, a fast and easy method for the detection of pathogens is required for early treatment of viral or bacterial infections in asthma exacerbation inpatients.
Patient characteristics stratified by age group are presented in Table 1.
Children under two years of age were admitted to the hospital significantly earlier after the onset of symptoms than older children, (p = 0.01, two-sample t-test). 61% of the children were discharged from hospital on the day of admission.
The most common respiratory manifestation was a cough (100%) together with an age-depending degree of wheezing (Table 1). At admission to the hospital, 92% of infants and children were diagnosed with an episode of troublesome lung symptoms lasting at least three days. Significantly more young children (less than three years of age) had objective wheezing and cough (asthma-like symptoms) than older children (p = 0.01, Z-score test). Previous and clinically significant chronic disease was diagnosed in 10% of the children. Of these 4/13 (31%) had previously diagnosed and current asthma, and had a severe exacerbation during the M. pneumoniae infection.
The majority of the patients (84%) had a chest x-ray taken, and 96% of these had positive radiological findings (Table 1). Among infants and young children, exclusive hilar adenopathy was more frequent, while older children usually had significant peripheral infiltration on the chest X-ray (Table 1). Children with atelectasis had a significantly longer duration of hospital stay; more than three days (35% versus 25%; p = 0.05). The rate of pulmonary complications was the same for children with CRP over 50 mg/l (POCT(Point of Care Testing), part of an adult definition of significant pneumonia) as below 50 mg/l (18% versus 19%, p > 0.05). No pulmonary complications were reported in the under two age-group. The number of severe manifestations of pneumonia was equal in the age-groups; 2–6 years and 7–15 years (Tabel 1). Overall 20% of the children had an increased CRP level of more than 50 mg/l, and they were all older than three years of age.
A total of 120 children received antibiotic treatment. The majority were treated with clarithromycin according to the local Guideline. Sixty-four patients, or 46%, were treated upon suspicion. Out of these, 53% had received other antibiotics (beta-lactam) prior to M. pneumoniae testing. Fifty-six patients (42%) were started on treatment upon receiving the positive test result. Only six children were treated with macrolide antibiotics twice due to suspicion of recurrence or treatment failure. One sample was tested for macrolide resistance and found negative.
The most common extra-pulmonary manifestation was nausea, with or without vomiting, reported by a third of all children. 23% of all children had some type of rash, and 9% had hives. In infants, there were skin manifestations in 33% of the cases. Two children developed Steven Johnson syndrome (SJS) with mucosal symptoms arising prior to or at the same time as the antibiotic treatment was started.
A total of 37 children had simultaneously been tested with sputum-culture for other bacterial pathogens. In 41% of these, a co-infection was diagnosed. The most common bacteria were Moraxella catarrhalis, Haemophilus influenzae and S. pneumonia. Due to methodological setup, all children were tested for Chlamydophila pneumoniae none were found positive.
Only two children were tested for viral infections during the clinical setup. The post-hoc analyses of 49 oropharyngeal-swabs showed that 27% of these had a single or mixed viral co-infection (RSV (1 child), influenza A (2), human metapneumovirus (1), rhinovirus (2), coronavirus (3), bocavirus (2) and adenovirus (5)). Four children were PCR positive for two viruses as well as for M. pneumoniae. Table 2 shows, in a similar matter as Table 1, the clinical characteristics of children with, without and of unknown viral infection. The data suggest that significantly more children with mixed infection of M. pneumoniae and a respiratory virus had rhinorrhoea (p = 0.02), and were wheezing (tendency, p = 0.07), compared to those who were only positive for M. pneumoniae. We could not identify other differences between the two groups, including no radiological discrepancies.
Antibiotic treatment of bacterial pneumonia must be sufficient in duration and, most crucially, early enough to prevent lesions forming that may resist both therapy and regeneration of normal lung parenchyma. The emphasis should be on early treatment and first treatment success in cases of calf pneumonia since the outcome for those animals that fail to respond successfully to first treatment is poor. Typically, one third to two thirds of animals that do not respond to initial therapy are permanently affected or lost.
The effectiveness of metaphylaxis (defined as mass medication of all animals on arrival in the feedlot) in reducing morbidity rates associated with pneumonia in feedlots is variable. A recent meta-analysis of North American studies estimated a decrease in mortality and morbidity of 2% and 26%, respectively for animals that received antimicrobial treatment on arrival in the feedlot. The average daily weight gain was 0.11 kg higher in these animals in comparison with calves not receiving metaphylactic treatment.
The use of antimicrobials for prevention (prophylaxis or metaphylaxis) of calf pneumonia has to be seen in the context of increasing pressure on the veterinary profession to promote prudent use of antibiotics, noting that indiscriminate use of antibiotics promotes the selection and subsequent proliferation of antibiotic-resistant strains of bacteria. The European Parliament recently called for a review of current practices of prophylactic use of antimicrobials.
Non-steroidal anti-inflammatory drugs (NSAIDs) have shown to reduce pyrexia, clinical signs, and lung pathology, and improve average daily weight gains in calves with respiratory disease compared to untreated calves or calves only treated with antimicrobials. Other studies, however, have not found significant differences between treatment groups. The cost-efficiency of additional anti-inflammatory therapy in bovine respiratory disease is uncertain.
It has been suggested that pneumonic animals should be isolated in appropriate facilities. However, there is little experimental evidence to quantify the benefits and it may lead to practical difficulties.
We present data from a large cohort of children with M. pneumoniae infection. All children enrolled were referred from the primary healthcare system to hospitalisation due to character and severity of symptoms. The majority of M. pneumoniae PCR test-positive children had LRTI, which we confirmed by a high rate of radiological findings (94%).
We found a higher rate of positive samples in the later wave of the epidemic in 2010 and 2011. School-aged children were more often M. pneumoniae positive (65%) than younger children, but even amongst the 2 to 6-year-old children 30% were M. pneumoniae positive substantiating our initial suspicion that M. pneumoniae also affects small children. Even a small number of infants; 6 out of 276 were diagnosed.
This study was conducted as a retrospective chart study. The doctor on call decided whom to test for M. pneumoniae. Children with M. pneumoniae infection might have been under-diagnosed if they had minor respiratory symptoms especially during the first wave of the epidemic period. Due to commonly held concepts of CAP epidemiology, originally based on a long-term study conducted in primary care from 1963–1975, we expect infants and young children to be under-diagnosed due to selection-bias.
Even very young children can become ill from M. pneumoniae even though it is less common. The differential diagnosis of respiratory viral infections and exacerbation of asthma-like symptoms must be considered. The clinical presentation with a cough, wheezing, low-grade-fever, CRP below 50 mg/L and rhonchi on auscultation in 33% of the youngest children can also be considered as a childhood asthma-like exacerbation, primarily due to viral infection in pre-school children. Indeed, we also had a minor degree of mixed viral co-infections discovered in our post-hoc analysis. It can only be speculated in what pathogen was the primary cause of disease in these cases. Due to our post-hoc findings, we would advise that small children with wheezing and rhinorrhoea should be tested for both M. pneumoniae and respiratory viral infections simultaneously. During the Norwegian M. pneumoniae epidemic, Inchly et al. described a similar relative number of viral co-infections.
In a Dutch childhood study of carriage of M. pneumoniae in the upper respiratory tract (URT), season and year of enrolment affected the prevalence of asymptomatic carries ranging from 3% to 52%. In our study, some of the children discharged from the ward on the same day as admitted to the hospital could have been carriers of M. pneumoniae. However, several of these children were treated with first-line antibiotics, prior to admission, and referred to our department because of insufficient response to beta-lactam antibiotic management.
Kroppi et al. found that 50% of children with LRTI caused by M. pneumoniae were co-infected with primarily S. pneumoniae or Chlamydiae spp. Only a small part of this cohort was tested for bacterial co-infection, but we did not regard this as a major problem. Again, it is noteworthy that 59% of the children had been treated with a beta-lactam antibiotic before examination for M. pneumoniae without improvement of the infection.
In parts of the same epidemic period in Denmark (2010–2011), Stockholm et al. identified an effect of azithromycin (a macrolide antibiotic) on episode duration of asthma-like symptoms in young children. No investigations for M. pneumoniae were done, and exclusion criteria of respiratory rate over 50/min, temperature over 39°C and CRP over 50 mg/L would not exclude all children with a possible M. pneumoniae infection [19–21]. Two recently published Norwegian studies described the discrepancy of the incidence of clinical symptomatic M. pneumoniae infections in preschool children between epidemic and endemic periods. Randomised Controlled Trials concerning the efficacy of macrolides on asthma-like symptoms should be conducted in endemic periods or better controlled for M. pneumoniae infections, especially in young children born after an epidemic period. The anti-inflammatory effect of macrolides still has to be further addressed.
10% of this cohort was affected by chronic illness, mainly respiratory severe illness. Severe asthma exacerbations were diagnosed in the current asthmatics.
Older children tended to be seen later after onset of symptoms and were accountable for the longer hospitalisations. This might indicate that older children had more severe infections, or that the delay in admission to the hospital resulted in more severe disease and thereby a prolonged period of rehabilitation. Despite that, we also identified severe pneumonia based on the radiological findings (atelectasis, pleural effusions) in the 2-6-year-olds. If adjusted for population size these preschool children had an increased risk of developing severe pneumonia compared with school children during this epidemic. Inchley et al. showed the same pattern even if their definition of severe pneumonia differed. Treating the infections earlier might reduce severe morbidity and length of hospital stays.
Treatment of M. pneumoniae infections with macrolide antibiotics is controversial since a Cochrane review, concluded that there is insufficient evidence to draw any specific conclusions about the efficacy of antibiotics in M. pneumoniae infections in children. The efficacy of antibiotic treatment should be discussed in light of a correct diagnostic test. Asymptomatic carriers of M. pneumoniae have to be differentiated from children suffering from symptomatic infections, LRTI, caused by M. pneumoniae. Gardiner et al. underline the need for RCT on this topic. In Denmark, SSI still recommends treatment of M. pneumoniae positive LRTI in children. Macrolide resistance is a growing problem worldwide. In Denmark, the occurrence is estimated to be 2%. No macrolide resistance was identified in our childhood cohort.
We found radiological changes in 94% of the chest x-rays taken in this study. The radiological findings were quite diverse, but notably, over 80% of children older than two years had a lobar infiltration while the younger children had significantly more subtle findings. This was in accordance with an Italian prospective childhood study.
Even in older children, symptoms could not be distinguished from CAP caused by other pathogens. Radiological findings in M. pneumoniae pneumonia were not distinguishable from CAP in general.
Almost 25% of all children had some kind of rash (erythema/hives) during the illness, and 33% had gastrointestinal symptoms like nausea and or vomiting. Severe extra-pulmonary manifestations accompanying respiratory infections caused by M. pneumoniae are expected to occur. Two children in our cohort were diagnosed with SJS, which is a known complication of M. pneumoniae. Outbreaks of M. pneumoniae–associated SJS in children has recently been reported. We did not see any children with neurological symptoms in this cohort which would be expected.
One nostril was closed off using an inflatable catheter as described previously.
Slowly, 10 ml of sterile Hanks balanced salt solution (without phenol) at body temperature was instilled via the catheter and left for 5 min. Lavage fluid was collected in tube for viral detection. The procedure was repeated in the other nostril. All used materials were sterile or disinfected using 70 % ethanol prior to use.
In all, 72 COPD patients with exacerbations that required ED visits were included in the study period. None of the patients were included twice. No patients received long-term oxygen therapy in this study. The mean FEV1 was 0.86±0.32 L (40.12%±15.70% of predicted value). The baseline characteristics of the 72 COPD patients, including age, sex, BMI, FEV1% predicted, FVC% predicted, GOLD stage, pack-years of tobacco use, previous inhaled or oral medications, peripheral blood WBC counts, and serum CRP and PCT levels are shown in Table 1. A total of 52 patients (72.2%) presented with two or more of the Anthonisen criteria, and 38 patients (52.8%) had recurrent exacerbations that required ED visits in the subsequent 1-year period. A total of 46 patients (63.9%) were admitted to ward and 26 patients discharged from the ED. Four hospitalized patients were admitted to the intensive care unit for acute respiratory failure, three of whom needed mechanical ventilator support, while the last received noninvasive ventilation support. None of the patients died.
Viruses were detected in the oropharynx of 16 (22.2%) of the 72 patients (Table 2). Parainfluenza virus type 3 (PIV3) was the most commonly detected virus (37.5%), followed by influenza A (Inf A) and human rhinovirus. Both adenovirus and PIV3 were identified in one patient. No influenza B or respiratory syncytial virus (RSV) was found. One patient had simultaneous detection of PIV3 and adenovirus. Patients with or without the confirmed presence of viruses were divided into two groups: 16 patients were virus-positive and 56 patients were virus-negative. There were no significant between-group differences in age, BMI, FEV1, FVC, length of hospital days, or number of exacerbation in the subsequent 1 year. Figure 1 shows the laboratory data at the time of ED admission of the 72 COPD exacerbation patients. WBC counts, CRP, and PCT levels were not significantly different between the virus-positive and virus-negative group. A larger proportion of the virus-positive patients had been previously treated with oral corticosteroids than had the virus-negative patients (37.5% versus 14.3%) (P=0.039). The viral-positive groups presented with more sore throat symptoms than did the viral-negative groups (62.5% versus 33.9%) (P=0.04). The family cluster of common cold symptoms was significantly higher for viral-positive groups than viral-negative groups (25% versus 1.8%) (P=0.001).
In all, 30 patients (41.7%) with COPD exacerbations had positive sputum bacterial cultures (Table 2). Haemophilus influenzae was the most commonly identified bacterial strain (30%), followed by Haemophilus parainfluenzae. The sputum bacterial culture of one patient grew Staphylococcus aureus and Acinetobacter baumannii. Chlamydia species were found by MRT-PCR in two cases, but no patients were positive for mycoplasma by PCR. There were no statistically significant differences between the bacteria-positive and bacteria-negative patients in age, BMI, FEV1, FVC, clinical symptoms, medications used prior to ED admission, length of hospital days, or recurrent exacerbations in the subsequent 1 year. WBC, CRP, and PCT levels were not significantly different between the bacteria-positive and bacteria-negative groups (Figure 2). Among the seven patients with PCT >0.5 ng/mL, three (42.9%) had sputum that was positive for bacteria growth, but none of these subjects were positive for viruses. The only significant difference was that the bacteria-positive group had a lower FEV1/FVC ratio than did the bacteria-negative group (52.43% versus 57.41%) (P=0.033). Both virus and bacteria were identified in five patients (6.9%). One had Inf A and Streptococcus pneumoniae, another had adenovirus and H. influenzae, the third had PIV3, adenovirus, and H. influenzae, the fourth had PIV3 and H. parainfluenzae, and the last had Escherichia coli and human metapneumovirus.
Table 3 shows the results of univariate and multivariate analysis of variables associated with recurrent exacerbations in the subsequent 1-year period. The results indicated that an increased sputum volume during the COPD exacerbation that required the ED visit was independently associated with a higher risk of a recurrent exacerbation during the subsequent year.
The percentage of patients free from readmission to the EDs in 1 year, analyzed by Kaplan–Meier curves and evaluated with the log-rank test, was not significantly different between the bacteria-positive and bacteria-negative groups. The curves for patients who were virus-positive and virus-negative also did not differ significantly (Figure 3). When the outcomes were analyzed specifically by PCT and CRP levels, the percentage of patients free from readmission to the EDs also showed no statistically significant differences (Figure 4).
Mechanical ventilation was required for 75 (72%) patients and lasted 13 [8–19] days. Of the 34 (45%) patients meeting criteria for ARDS, 4 required extracorporeal membrane oxygenation. Vasoactive agents were required for 41 (39%) patients, and renal replacement therapy was started for 10 (10%) patients.
The first-line antibiotics were active on MP and CP in 62 (60%) patients. Time from ICU admission to antibiotic initiation was 1 [0–4] day. Combination therapy was used in 61 (59%) patients and consisted to a third-generation cephalosporin (C3G) and a macrolide in 24 (39%) patients, a C3G and a quinolone in 13 (21%) patients, another betalactam and a macrolide in 16 (26%) patients, another betalactam and a quinolone in 6 (9%) patients, or another antibiotic and a macrolide in 2 (3%) patients. Antibiotics was adapted according to microbiology results with a macrolide (n = 72), a quinolone (n = 24) or a cycline (n = 3).
All authors read and approved the final manuscript. KYL had primary responsibility for the study concept and design, and writing the manuscript. YSY participated in preliminary data collection, data analysis, and writing the manuscript. JYH and JUR participated in patient care, data collection, and data analysis. JHK contributed to interpretation of the data and editing of the manuscript. JSL supervised the design and execution of the study. JCK read the chest radiographs.
After a clear diagnosis of severe pneumonia, collecting blood for bacterial culture and sensitivity test was performed prior to the use of antibiotics when conditions permitted. A separate venous access for antibiotics was established as much as possible, to rationalize the use of antimicrobial drugs and avoid side effects. In principle, the application of antimicrobial drugs was carried out on the basis of evidence-based medicine, but a majority of them are classified as empirical treatment. As the therapeutic window of children with severe pneumonia was very small, the initial drugs for treatment covered an antibacterial spectrum as broad as possible, as well as all the pathogens. There were sufficient data displaying that the inappropriate choice of anti-infective drugs for initial therapy and untimely appropriate treatment (effective therapy of antigens) had adverse consequences on the prognosis. The main indicators of efficacy were a decrease in body temperature, improvement in poisoning symptoms and ability to drink water or conduct breast-feeding or food intake. In general, 3–5 days after the body temperature became stable, the drug dosage was reduced and gradually discontinued.
Intravenous injection of immune globulin is considered a safe and effective method for the treatment of children with severe pneumonia. It can rapidly improve immunoglobulin G (IgG) levels in the patient's blood; enhance the body's resistance to infection and immune function. By passively accepting lgG, the body acquires resistance to a variety of microbial infections. High-dose intravenous IgG infusion can increase the IgG concentration 3- to 6-fold in circulating blood compared to a normal person. Therefore it has the ability to prevent infections. Using IgG infusion concurrently with antibiotics can be used to treat bacterial infections and has a broad anti-bacterial and viral spectrum, as well as a dual function of anti-bacterial antigens and viral antigens.
In summary, positive and effective nursing can promote the rehabilitation of children patients, reduce the incidence of complications and children's mortality, thus play an important role in the rehabilitation of children with severe pneumonia. Psychological counseling may also be strengthened. Children feel a sense of inadaptation with regard to unfamiliar environment by instinct. They cried and even refused infusion in the face of examination and treatment by strangers. Therefore, nurses must be careful and gentle to children patients. For older children, they were able to explain to them the importance of the infusion and blood tests for the treatment of the disease, and increase their sense of trust in the medical staff. Health education is also essential, nurses should communicate more with parents and acquaint them with relevant knowledge and inform them regarding the prevention and treatment of diseases, such as that children usually need to do exercise, enhance nutrition, bask more in sunshine and engage in outdoor activities, ensure adequate sleep, pay attention to personal health, and get vaccinated for the prevention of pneumonia and influenza if necessary.
The initially described coronavirus strain 229E has been previously identified as the second most frequent cause of common cold after rhinoviruses in healthy adults. Predominant symptoms were acute rhinorrhea, nasal congestion, and/or sore throat [9, 10]. Nasal discharge was the hallmark of all symptoms after inoculation of HuCoV-229E to healthy volunteers, and further observed symptoms were malaise, headache, chills, and cough.
HCoV-229E has been associated with bronchitis, acute exacerbations of COPD, and pneumonia in infants, children, and elderly persons with underlying illnesses [11–13]. Life-threatening infections have only been described in immunocompromised patients [7, 8], but the correlation of HCoV-229E with LRTI in healthy adult individuals is uncertain. An adult patient with pneumonia tested positive for HCoV-229E has been described in a study conducted in rural Thailand, but it is not made clear if other comorbidities were present. Nine Italian patients hospitalized with LRTI have also been tested positive for HCoV-229E; however, their age is not specified. Αlthough numerous studies have tentatively linked 229E infections to severe respiratory tract illness over many years, no study controlling for age and underlying illness has demonstrated an epidemiologic association between infection with HcoV-229E in healthy adults and any illness other than the common cold. Furthermore, no case of HCoV-229E-associated ARDS has been reported in immunocompetent adults. Only a few cases of pulmonary infection and ARDS have been described in a 76-year-old woman infected with the closely related alpha coronavirus HCoV-NL63 and in a 39-year-old woman with poorly controlled DM and infected with the beta coronavirus HCoV-OC43.
The patient was a teacher and thus exposed to multiple pathogens from her students. She was an immunocompetent adult with no underlying disease. Her symptoms progressed rapidly, despite the immediate administration of broad-spectrum antibiotics, and clinical, laboratory, and radiologic findings were compatible with ARDS. The patient came very close to intubation and mechanical ventilation, but early addition of corticosteroids in her therapeutic regimen seems to have played a decisive role towards her favorable outcome. Close monitoring and continuous recording and assessment of her vital signs warranted the borderline avoidance of her transfer to the ICU.
HCoV-229E was isolated twice from the patient's nasal secretions; she was not intubated, and thus, the BAL sample was not taken. Extensive workup did not reveal any immune defect; all microbiological and serological studies remained negative for other pathogens. Rapid and reliable diagnosis of human coronavirus infections is of pronounced clinical importance. New RT-PCR methods in sputum and nasal aspirates successfully have diagnosed human coronavirus infections. Multiplex RT-PCR is used increasingly to diagnose respiratory infections and has shown to be more sensitive than viral culture and antigen detection and also rapid and cost-effective, with greater sensitivity and similar specificity compared to real-time RT-PCR.
A 76-year-old Caucasian man who underwent laryngectomy 10 years earlier, presented with fever (38.9 °C; 102.0 °F), increased sputum production, and purulent conjunctivitis. These symptoms emerged gradually over a period of 48 hours. He noted increasing difficulty in coughing out his sputum that became brownish and viscous. He had been wearing a heat and moisture exchanger (HME) filter that covered his stoma and spoke through a tracheoesophageal voice prosthesis. The symptoms started a day after a very cold weather spell with temperatures of −7 to −1 °C (19–31 °F). He had to remove his HME on several occasions for extended periods of time to enable him to breathe when he walked outside his home.
His past medical history included hypopharyngeal squamous cell carcinoma which was treated with intensity-modulated radiotherapy (IMRT) 12 years earlier. A recurrence of the cancer 2 years later required laryngectomy. He had no signs of tumor recurrence since then. He also suffered from paroxysmal hypertension, diverticulitis, and migraines.
He was vaccinated with the current Influenza virus vaccine 3 month earlier. He had also received a pneumococcal polysaccharide vaccine (PPSV23) 2 years earlier.
He was in mild respiratory distress especially when coughing. He had coughing spells and expectorated green-brown dry and viscous sputum. A physical examination revealed bilateral purulent conjunctivitis and auscultation of his lungs revealed coarse rhonchi and no crepitations. No lymphadenopathy was noted. The results of the rest of the physical and neurological examinations were within normal limits. A chest X-ray was normal.
Sputum and conjunctival culture grew heavy growth of beta-lactamase-producing nontypeable Haemophilus influenzae (NTHi) that was susceptible to levofloxacin and amoxicillin- clavulanate. A FilmArray® Respiratory Panel 2 (RP2) polymerase chain reaction (PCR) system test did not detect 14 viruses (adenovirus, coronavirus HKU1, coronavirus NL63, coronavirus 229E, coronavirus OC43, human rhinovirus/enterovirus, human metapneumovirus, influenza A, influenza B, parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, respiratory syncytial virus) and four bacteria (Bordetella pertussis, Bordetella parapertussis, Chlamydophila pneumoniae, Mycoplasma pneumoniae).
He was treated with orally administered levofloxacin 500 mg/day, ciprofloxacin eye drops, acetaminophen, and guaifenesin. Humidification of his trachea and the airway was maintained by repeated insertions of 3–5 cc respiratory saline into the stoma at least once an hour and by breathing humidified air.
The main challenge was to maintain a patent airway as the mucus was very dry and viscous and tended to stick to the walls of his trachea and the stoma. The mucus had to be repeatedly expectorated by vigorous coughing and by manual removal from the upper part of his trachea and stoma.
He experienced repeated episodes of sustained elevated blood pressure (up to 210/110) and tachycardia (112/minute). This was managed by administration of clonidine 0.1 mg as needed (1–2/day).
His fever started to decline 48 hours after antimicrobial therapy was started. The conjunctivitis improved within 36 hours. The sputum production declined and became less viscous over time, but persisted for 5 days.
Antimicrobial therapy was discontinued after 7 days.
His condition improved and he had a complete recovery in 7 days. He was seen in the clinic every 2 months and showed no recurrence of his infection for the following 8 months. He received vaccination for H. influenzae B and Prevnar 13® (pneumococcal conjugate vaccine; PCV13) 4 weeks after his recovery.
In this study, we have focused on inward patients only. Therefore, we may have missed a significant number of outpatients, who would have had milder form of hMPV associated ARTI.
IAV are a major cause of respiratory tract infections and cause excess morbidity and mortality every year. In addition to seasonal outbreaks of influenza epidemics in the winter months, novel influenza viruses are occasionally introduced into the human population and cause pandemics. The introduction of IAV of the H1N1, H2N2 and H3N2 subtypes have caused pandemics in 1918, 1957 and 1968 respectively. More recently, H1N1 viruses of swine origin caused the first pandemic of the 21st century, which started in Mexico in March 2009,. The virus spread rapidly over all continents and caused disease especially in children and young adults.
In addition, avian IAVs are occasionally transmitted from infected poultry to man. Especially highly pathogenic avian influenza viruses of the H5N1 subtype cause infections of humans relatively frequent and 60% of these cases have a fatal outcome,.
To protect individuals against seasonal IAV infection, vaccination is the preventive measure of choice. Especially individuals with high risk to develop complications of IAV infection benefit from vaccination, like the elderly, patients with chronic diseases and immunocompromised individuals. In addition, vaccination could help to mitigate the impact of a pandemic outbreak. However, there are three scenarios in which vaccination cannot be used effectively. First, certain high risk group respond to vaccination poorly like the frail elderly and certain immunocompromised subjects. Secondly, in case of antigenic mis-match, the vaccine may induce antibodies that fail to neutralize the epidemic strains optimally and therefore do not afford protection against theses drift variants,. Finally, in case of a pandemic the vaccines may become available too late as was the case during the 2009 pandemic.
Under circumstances mentioned above, antiviral drugs may be used to treat patients infected with IAV and, alternatively, such drugs can be used prophylactically in outbreak situations.
At present, two classes of licensed antiviral drugs against influenza exist. The first are the adamantanes (amantadine and rimantadine) which inhibit the proton-channel function of the Matrix2 (M2) protein. This protein functions as an ion-channel and plays a role in the uncoating of the genetic material which is an essential step in the virus replication cycle.
The other class of antiviral drugs comprises the neuraminidase (NA) inhibitors, zanamivir and oseltamivir. NA acts as a receptor destroying enzyme and plays a role in the release of viral particles that bud from infected cells. NA inhibitors are analogs of sialic acid, the substrate of the enzyme. The use of these drugs reduces virus replication and may reduce the duration of influenza illness,,.
Unfortunately the use of these antiviral drugs also has some drawbacks. Especially the use of M2 inhibitors may cause some side effects including neurological and gastrointestinal symptoms. The main drawback of the use of both M2 and NA inhibitors is the emergence of resistant strains which are positively selected rapidly. For example, seasonal H3N2 IAV resistant to amantadine emerged in 2000 in Asia and is the predominant strain ever since. Furthermore, 15.5% of the H1N1 viruses were resistant to adamantanes in 2005–2006 worldwide. In addition, most of the seasonal H1N1 viruses isolated in the influenza season 2008–2009 were resistant to oseltamivir,,. Also during the treatment of especially immunocompromised patients, which shed virus for extensive periods, the emergence of resistant strains can be a complication.
Clearly there is a need for novel drugs that can be used to treat IAV infection and that do not suffer from these disadvantages.
Therefore, we wished to assess the antiviral properties of recombinant SP-D from human (RhSP-D) and porcine (RpSP-D) origin to various IAV and their potential as an antiviral drug. It is hypothesized that IAV less likely will develop resistance to this class of antiviral molecules since they target glycans present on IAV. SP-D belongs to the collectin family, which is an important class of innate immunity proteins involved in the early response against pathogens. These collagenous C-type lectins are mainly produced by Clara cells and type II pneumocytes. They can neutralize a variety of respiratory pathogens including bacteria and viruses such as respiratory syncytial virus, parainfluenza virus, adenoviruses, SARS coronavirus and IAV (for review see,). Collectins can bind glycoconjugates expressed on the surface of these pathogens via their carbohydrate recognition domains (CRDs).
The importance of SP-D is demonstrated by studies with SP-D knock-out mice that are more susceptible to infection with IAV than SP-D competent mice. Furthermore, it has been shown that the SP-D concentration increases during IAV infection and that the administration of an SP-D inhibitor during infection of mice increased the lung virus titer compared to a normal infection.
The favourable biological properties of SP-D in vivo prompted further investigation of this molecule as an antiviral drug. Especially porcine SP-D (pSP-D) showed promising results in vitro,,. It exhibits unique structural features compared to SP-Ds from other animal species. Unlike its human counterpart, it contains an extra cysteine in the collagen domain, it is N-glycosylated with a sialic acid-rich oligosaccharide in the CRD and there is a potentially important extra loop region (SGA) present in the CRD which could play a role in the sugar-binding properties of pSP-D. It was shown with pSP-D isolated from porcine bronchoalveolar lavage that pSP-D displays a higher affinity to IAV than human or rat SP-D. Since only a limited number of IAVs was tested in previous studies, it still remains unknown what range of IAV strains can be neutralized by pSP-D and by hSP-D.
In the present study, we investigated the potential of RpSP-D and RhSP-D to neutralize IAVs of the H1N1, H3N2 and H5N1 subtypes.
These findings indicate that RpSP-D has broadly neutralizing activity and may be a promising candidate as an antiviral drug for the treatment of IAV.
To our knowledge, it is the first time that human coronavirus HCoV-229E has been detected in severe lower respiratory tract infection with ARDS of a healthy adult with no comorbidities. Although it is considered as a “benign” microorganism and linked to mild respiratory symptoms, the presence of HCoV-229E should not be underestimated and considered as a possible pathogen even in coinfections with other microorganisms and in more serious LRTIs. The reason why HuCoV-229E causes different clinical manifestations in diverse patient groups has not yet been answered. The process through which HCoV-229E may evade normal immune defense and cause life-threatening illness remains to be elucidated.
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.
During the hospitalization, six patients (21.4%) required oxygen supplement therapy: four with nasal cannula and two with face mask. No one required mechanical ventilator or ECMO therapy. Nineteen patients (67.9%) received lopinavir/ritonavir for antiviral therapy. Ultimately, pneumonia was present in 22 patients (78.5%) and the proportion of pneumonia was 91.3% (21/23) among the patients who received a CT scan (Table 2). Seventeen patients (60.7%) developed fever and became afebrile during the hospitalization and the median day of defervescence was 9 days (range, 3–18) after symptom onset (Supplementary Fig. 1). By February 17, 10 patients were off isolation or discharged, and the median day of off-isolation/discharge was 18.5 days after symptom onset (range, 11–27).