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Inhaled bronchodilators, LAMA and LABA, are the main pharmacological therapies in stable COPD patients (Tashkin et al., 2008; Wedzicha et al., 2008; Vestbo et al., 2013). Although Vogelmeier et al. (2011) reported that the tiotropium (LAMA)-treated group had a lower exacerbation rate than the salmeterol (LABA)-treated group in their head-to-head study, both LAMA and LABA treatments decreased exacerbation rates and improved lung function or health-related quality of life. Tashkin et al. (2009) found that combination LAMA/LABA therapy improved pulmonary function (FEV1.0) and respiratory symptoms better than LAMA therapy alone. ICS, the main treatment for asthma, is also prescribed in COPD patients and may reduce airway inflammation and decrease exacerbation rates only in moderate and severe COPD patients (Calverley et al., 2007). Treatment with macrolide antibiotics has been reported to prevent COPD exacerbations and improve patient quality of life and symptoms, especially in patients who have frequent exacerbations (Albert et al., 2011; Yamaya et al., 2012a), although this intervention could lead to unfavorable events such as increasing the prevalence of macrolide-resistant pathogens or cardiac toxicity.
It has been estimated that most exacerbations of COPD are due to respiratory viral and/or bacterial infections. Thus, the major pharmacological components of managing exacerbations of COPD include SABAs, short-course systemic glucocorticoids, and antibiotics (Vestbo et al., 2013). However, anti-viral therapies are rarely prescribed, because specific anti-viral therapies do not exist, except for influenza virus and RSV. Treatment for influenza appears appropriate in patients with COPD (Harper et al., 2009), while the utility of treatment for RSV has not been confirmed in adults. It is doubtful that systemic corticosteroid treatment affects the clinical course of respiratory viral infections. Lee et al. (2011) showed that short-course systemic steroid treatment did not affect viral load or shedding, and humoral immunity may be diminished by steroid treatment.
Some research has shown that LAMA may affect viral infections. Tiotropium, one of the LAMAs, may inhibit HRV and RSV infections by reducing the levels of intercellular adhesion molecule-1, which is the binding site for most HRVs (Iesato et al., 2008; Yamaya et al., 2012b).
The need for informed consent was waived in view of the observational nature of the study with no interventions performed. The protocol and standardized clinical form, including the waiver of informed consent, were approved by the Asan Medical Center Institutional Review Board (IRB number: 2010-0079).
Verbal consent was obtained from parents/legal tutor and subjects before screening to determine eligibility. Once a patient was determined to be eligible for study participation, written informed consent and assent (for children older than 8 years) were obtained. The protocol was approved by the institutional review board of each hospital.
Since specific therapy is limited to only several antiviral agents, prevention of viral infections is crucial to reduce the incidence and mortality of viral diseases. According to the different periods of transplantation, the strategies might be divided to prophylaxis pre-transplantation, during transplantation and post-transplantation. Before transplantation, selection of virus-seronegative stem cell donors for seronegative recipients, and decreasing virus loads in virus-seropositive donors and recipients should be considered. During transplantation, the strategies of conditioning and GVHD prophylaxis should be chosen prudently to minimize the delay of immune reconstitution. After transplantation, prophylaxis should be performed throughout the risk period such as pre-engraftment and GVHD. The incidence of HSV and VZV infections has decreased from 80% to lower than 5% in the recipients of allo-HSCT receiving antiviral prophylaxis throughout the risk period. Preemptive therapy for reactivation of some latent viruses, such as CMV and EBV has been demonstrated to reduce the progression of viral diseases. Vaccination, such as Measles–Mumps–Rubella and VZV vaccine, seems useful to prevent corresponding viral infections. Influenza virus vaccine is suggested to be given to the recipients prior to each influenza season.
Although multiple strategies have been used, the treatment of viral diseases remains rather a challenge because few agents are available and efficacious. In the recipients of allo-HSCT, immunotherapeutic strategies to restore virus-specific immunity, such as reducing immunosuppressants, DLI and ex vivo generation of virus-specific CTL, are now advocated in the treatment of viral diseases. However, reducing immunosuppressants is unfeasible in many patients due to potential risk of GVHD, and DLI is limited by unavailable stem cell donors and the risk of exacerbating GVHD. Of note, these adoptive cellular therapies are only proven efficacious for a few viruses, such as CMV, EBV and adenovirus. Early intervention has a dramatic influence upon survival and may reduce the extent of permanent injury in survivors. For example, in patients with CARVs infections, treatment is more effective if started prior to development of lower respiratory tract infection (LRTI) or respiratory failure. Our data showed that the patients with EBV fever without tissue involvement had better treatment response than those with end-organ diseases or PTLD.
The study was performed at a medical ICU of the Asan Medical Center, a tertiary referral hospital in Seoul, Republic of Korea. This university-affiliated teaching hospital has 2700 beds and eight ICUs. During the study period, most of the adult patients with severe HAP requiring ICU care were referred to the medical ICU. The medical ICU is a closed 28-bed unit managed by five board-certified intensivists. All intensivists attend structured twice daily bedside rounds. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was preferably performed on patients with bilateral interstitial pattern infiltration or non-resolving pneumonia, at the discretion of the physician’s judgment. The BAL protocol has been described in detail elsewhere.
The term “virus-induced exacerbation” is not uncommon, but only a small number of prospective studies have been conducted so far (Nicholson et al., 1993; Johnston et al., 1995). Importantly, respiratory infections do not always result in an exacerbation, and there is little evidence that treating or preventing the infection may cure or prevent an exacerbation (Xepapadaki and Papadopoulos, 2010). However, another study found that URT infections were strongly associated with exacerbations of asthma leading to hospital admission, in both adults and children (Johnston et al., 1996), and they may have contributed to asthma mortality, especially in the setting of hospital admission. Specific anti-viral therapies have not been established except for influenza viral infection, which have been recommended for persons with asthma or COPD. Furthermore, regarding preventive therapy for RSV, palivizumab as described above is now commercially available, and it might be appropriate for infants and young children with congenital heart disease, bronchopulmonary dysplasia, and prematurity before 35 weeks of gestation (Dawson-Caswell and Muncie, 2011). Blanken et al. (2013) stated that palivizumab treatment in healthy preterm infants born at a gestational age of 33–35 weeks reduced the number of wheezing days during the first year of life.
In this regard, several therapeutic strategies would need to be taken early in the course of infection to maximize the effects of treatments such as systemic corticosteroids, antibiotics if necessary, and short-acting β-agonist inhalers (SABAs), followed by inhaled corticosteroid (ICS) and long-acting β-agonist combination (LABA) therapy. Kerstjens et al. (2012) reported that additive long-acting muscarinic antagonist (LAMA) therapy with tiotropium (known as a cornerstone of COPD treatment) significantly increased the time to the first exacerbation and improved FEV1.0 in poorly controlled asthmatic patients with standard therapy (ICS and LABA). Similarly, tiotropium improved lung function and reduced the chance of rescue inhaler (SABA) in patients with overlap syndrome (Magnussen et al., 2008).
In consequence of the diagnostic uncertainty for M. pneumoniae infections, the British Thoracic Society guidelines suggest empiric macrolide treatment at any age if there is no response to first-line β-lactam antibiotics or in the case of very severe disease (Harris et al., 2011). The lack of a cell wall makes M. pneumoniae resistant to cell wall synthesis inhibitors such as β-lactam antibiotics. The antibiotics with the best minimum inhibitory concentration values against M. pneumoniae include macrolides, tetracyclines, and fluoroquinolones (Waites and Talkington, 2004). Although the latter two have a good in vitro inhibitory effect against M. pneumoniae, tetracyclines may cause teeth discoloration (Waites and Talkington, 2004) and fluoroquinolones may affect the developing cartilage in young children (Adefurin et al., 2011). Thus, they are not recommended by current guidelines in young children; the age limit for tetracyclines is ≥8 years, while that of fluoroquinolones is adolescence with skeletal maturity (Bradley et al., 2011). The occurrence of arthropathy due to fluoroquinolones, however, is uncertain, and all musculoskeletal adverse effects reported in the literature had been reversible following withdrawal of treatment (Adefurin et al., 2011). The protein synthesis inhibitors of the macrolide class have a more favorable side effect profile and are therefore the first-line antibiotics for M. pneumoniae infections in children (Bradley et al., 2011).
Although antibiotics are effective against M. pneumoniae in vitro (Bebear et al., 2011), there is lack of evidence on their in vivo efficacy. Observational data indicated that children with CAP due to M. pneumoniae have a shorter duration of symptoms and fewer relapses when treated with an antimicrobial agent active against M pneumoniae (McCracken, 1986; Waites and Talkington, 2004). A recent Cochrane review evaluated seven studies on the effectiveness of antibiotic treatment for M. pneumoniae lower respiratory tract infections in children (Gardiner et al., 2015). However, the diagnostic criteria, the type and duration of treatment, inclusion criteria, and outcome measures differed significantly, making it difficult to draw any specific conclusions, although one trial suggested that macrolides may be efficacious in some cases (Esposito et al., 2005). It is clear that studies on the efficacy of antibiotics rely on a correct diagnosis of M. pneumoniae infections. Given the aforementioned shortcomings of current diagnostic tests, conclusions on the efficacy of antibiotic treatment will have to be re-examined.
Management of NP relies upon expert opinion, and results of retrospective observational studies from mainly single centers, as to date no randomized-controlled trials comparing different treatments have been performed. A multi-disciplinary team of pediatric respiratory physicians, intensivists, thoracic surgeons, and infectious diseases experts is often required. The overarching aims are to control and ultimately reverse the pathobiologic changes associated with NP. These include providing supplemental oxygen to relieve hypoxia, ensuring adequate analgesia to reduce pleuritic pain and improve ventilation, administering prolonged antibiotic therapy, and decreasing any mass effect or intrathoracic pressure by draining gas and/or intrapleural fluid [50, 80, 81, 86, 96]. Correcting fluid and electrolyte abnormalities and attention to nutrition, including managing hypoalbuminemia, is also important. Some children will require circulatory and ventilation support, while occasionally extracorporeal membrane oxygenation (ECMO) is used in those with refractory hypoxemic respiratory failure [19, 23, 28]. Severely ill children with suspected or proven S. aureus or S. pyogenes infection—especially with bilateral lung involvement, pulmonary hemorrhage, or impaired circulation—may also benefit from high-dose intravenous (IV) immunoglobulin infusion (2 g/kg), which is repeated after 48 h if there is no improvement [66, 97].
A prolonged course of IV antibiotics is the cornerstone of therapy. The initial choice of antibiotics in otherwise healthy, fully immunized children should be the same as for empyema and cover gram positive organisms, especially pneumococci, S. aureus and S. pyogenes, taking into account local epidemiologic and microbiologic data. Consequently, the recommended first-line treatment of IV penicillin or ampicillin for children hospitalized with severe but uncomplicated CAP [98, 99] will need broadening to include beta-lactam anti-staphylococcal antibiotics, such as oxacillin or flucloxacillin [28, 33]. Treatment can then be tailored according to microbiological results, although these may only be positive in 8–55% of cases (Table 1). When suspicion of MRSA is high (eg. local prevalence >10%, ethnicity, recent personal or household history of skin infections) or if it is confirmed by culture, antibiotics should be directed against this specific pathogen. Importantly, vancomycin penetrates poorly into lung parenchyma and treatment failures can occur in up to 20% of MRSA pneumonia when used as monotherapy. Thus, until MRSA is confirmed, a beta-lactam anti-staphylococcal antibiotic should be part of the treatment regimen. While high-level evidence is lacking, the addition of agents such as linezolid, clindamycin, or rifampicin capable of inhibiting protein synthesis (including toxin production) may result in better outcomes for those with S. aureus or S. pyogenes infections [21, 99]. When NP complicating an M. pneumoniae infection is suspected, a macrolide such as IV clarithromycin or azithromycin is added. However, these agents should not invariably replace antibiotics active against pneumococci and S. aureus, given the high rates of mixed infection associated with M. pneumoniae pneumonia, frequent negative microbiology results in patients with NP, and increasing levels of macrolide resistance in respiratory bacterial pathogens. Finally, the initial empiric antibiotic therapy may need to provide extended gram negative coverage by including a third or fourth generation cephalosporin if the child is unimmunized against H. influenzae type b (Hib), immunocompromized, or if the infection was hospital-acquired.
The optimal duration for antibiotic treatment of NP is unknown. The median length of antibiotic courses in case series listed in Table 1 range from 13 to 42 days, with 3 of the 5 studies providing these data reporting a median antibiotic course duration of 28 days [28, 33, 36]. Switching from IV to oral antibiotics is appropriate once the child is afebrile for at least 24 h and no longer showing signs of sepsis, their respiratory distress is resolving, enteral feeds are being tolerated, and inflammatory markers are declining. At this point antibiotics are continued for at least another 10–14 days, a recommendation that aligns with consensus guidelines for PPE and empyema complicating pediatric CAP [86, 99].
Nasopharyngeal swab specimens were collected from enrolled patients, placed in a tube with viral transport media, and maintained under refrigeration until they were sent to the Molecular Biology Laboratory of the Infectious Diseases Department, Instituto Nacional de Ciencias Médicas Salvador Zubirán, where they were stored at −70°C. Samples from the patients enrolled in San Luis Potosí were maintained under refrigeration and transported to the Medical School (Universidad Autónoma de San Luis Potosí) where they were stored at −70°C until they were sent to the Instituto Nacional de Ciencias Médicas Salvador Zubirán for storage and virological testing; the samples sent from San Luis Potosí to Mexico City were shipped on dry ice.
All nasopharyngeal swabs were tested by real‐time polymerase chain reaction (RT‐PCR) for influenza A following the Centers for Disease Control and Prevention protocol as described previously.12 Respiratory samples were also tested with the RespiFinder 19 (April 2010 to May 2012) or RespiFinder 22 (previously RespiFinder Plus, June 2012 to March 2014), from PathoFinder BV, Maastricht, the Netherlands. This multiplex RT‐PCR test can detect and differentiate 15 viruses (coronavirus NL63, OC43, and 229E, human metapneumovirus, influenza A, influenza AH5N1, influenza B, parainfluenza virus types 1 to 4, RSV A and B, rhinovirus, and adenovirus), as well as four bacteria (Bordetella pertussis, Chlamydophila pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae). RespiFinder 22 removed influenza H5N1 and added bocavirus (type 1), coronavirus HKU1, influenza A H1N1v, and enterovirus.
We have reported and described the prevalence of virus-positive respiratory samples taken at the time of intubation in ventilated adults, contributing to improving epidemiological knowledge in the critical care setting. Using the most sensitive methods for viral detection, we were able to identify that 22% of our patients had viruses in their airways. The detection of respiratory viruses in the respiratory tract, however, was not always associated with respiratory symptoms, as demonstrated by the 12% asymptomatic carriage in group 2 (Figure 3, group 2). Finally, we suggest that patients with viruses in the respiratory tract and respiratory symptoms (suggesting a virus-associated respiratory disorder) had a better prognosis in the ICU than patients without viruses and respiratory symptoms (suggesting other causes of respiratory disorder), as shown in Figure 3 (group 1). Further studies are necessary: first, to confirm the importance of viral infections as a cause of acute respiratory failure in patients admitted to the ICU; and, second, to address the role of antiviral therapy in this population.
The present study reports that respiratory viruses, as systematically screened with sensitive methods at the time of intubation, are common (22%) among adults ventilated for more than 48 hours, regardless of the reason for admission to the ICU. Rhinovirus was the most commonly isolated virus. We have identified, for the first time in this setting, three risks factors associated with a virus-positive sample – namely, admission with respiratory disorder, COPD/asthma and admission during the winter endemic viral season. These factors highlight that the diagnosis of respiratory viral infection should be focused for patients with a respiratory disease, and support the hypothesis of the clinical impact and pathogenic role of viral infection. In addition, we suggest that the ICU mortality might be lower in viral-associated respiratory disorder than in nonviral-associated respiratory disorder. A virus-positive sample had no impact on the time to ventilator-associated pneumonia, as previously reported in a smaller sample of this cohort.
Our finding differs from previous studies assessing the microbiologic pattern of severe pneumonia or acute exacerbation of COPD, which reported a lower prevalence of respiratory tract viral infection, varying from 0% to 16%. Differences in the diagnosis tests, the lack of a PCR assay and the limited range of viruses sought may explain this differential. Our rates of virus-positive respiratory samples were consistent with the prevalence of respiratory tract viral infections of 17–48% observed in recent prospective studies using molecular methods for viral detection and focusing on COPD patients or patients admitted to the ICU for cardiorespiratory failure. As previously reported, the prevalence of virus-positive respiratory samples was increased in the endemic viral period.
The molecular method used in this study for viral detection is recognised as the most sensitive technique. Nonetheless, the clinical relevance of a positive respiratory virus PCR test needs to be appraised. This topic has been discussed in specific populations that differed from our ventilated ICU patients; however, no chronic shedding or carriage of respiratory virus RNA was found in children and no chronic shedding or carriage of respiratory syncytial virus was found in COPD patients. Rhinovirus RNA could be detected up to 2–3 weeks after infection, without exceeding five weeks and virus influenza RNA could be detected up to seven days after infection. These findings suggest that PCR-positive patients had been infected recently in our study, most of them within the two weeks before admission.
According to previous studies focusing on patients at high risk for viral disease, rhinovirus and virus influenza were the most frequently recovered viruses. These epidemiological data underscore the potential pathogenic role of rhinovirus and of influenza virus as the cause of severe respiratory disorder.
In the present study, the proportion of rhinovirus (42%) was higher than reported in ICU patients. While its role as an important respiratory pathogen remains the subject of debate, several experimental studies with nasal inoculation demonstrated that rhinovirus could reach, penetrate and replicate in the lower airway epithelium and could induce a proinflammatory response. Rhinovirus was also associated with severe lower respiratory tract illness.
In contrast, influenza virus is recognised to play a major pathogenic role during flu outbreaks in the winter-spring season. A causal relationship between influenza virus infection and hospitalisation for respiratory or cardiac failure has been shown in vaccine effectiveness studies.
We failed to demonstrate that patient exposure to respiratory viruses significantly increased the risk of ventilator-associated pneumonia. It is commonly reported that respiratory viruses could facilitate bacterial infection of the airways, by damaging the respiratory epithelium. Some experimental studies have reported that respiratory viruses may promote bacterial adhesion to respiratory epithelial cells, a process that may increase bacterial colonisation, and that rhinovirus may increase the ability of Staphylococcus aureus to internalise into pneumocytes with a mechanism that involves the virus-induced release of IL-6 and IL-8 and the overexpression of ICAM-1. Finally, an epidemiological association has been described between viral pneumonia and nosocomial infection or respiratory sepsis.
In the subgroup of patients with respiratory disorder, those with virus-positive samples surprisingly had a better survival. This result should be interpreted cautiously because it relies on the control group (that is to say, patients with a virus-negative sample). This finding does not question the severity of virus-associated respiratory disorder, but simply suggests that the prognostic may well differ from other causes of respiratory disorder. It has been reported that the clinical severity and inflammatory responses in COPD exacerbations could be modulated by the nature of the infecting organism.
We are aware of limitations. The monocenter design of the study, the relatively small number of included patients, patients' underlying disease heterogeneity as well as the fact that 18 patients (8.7%) were eligible but not screened may limit the interpretation and relevance of our data. Because the systematic search for bacteria was not obtained at the time of intubation, 'virus-associated respiratory disorder' does not necessarily mean virus-induced respiratory disorder. In addition, the PCR might be too sensitive and we cannot exclude an asymptomatic carriage of respiratory viruses in the airways in some cases. In the future, a quantifying viral load might be another approach to improve the diagnostic accuracy.
The results reported here may have important implications for the design and power analysis of a randomised controlled trial using antiviral drugs. With a 12% mortality rate in the control group (that is to say, the rate we observed in virus-associated respiratory disorder), the room for improvement in patients with viral pneumonia would be lower than that for respiratory disorder overall (34%). An appropriate sample size would consequently be necessary to demonstrate the clinical impact, if any, of antiviral drugs.
This is a retrospective and observational study in which data from children and adolescents under 18 years of age, visited to one of the 117 Emergency Departments (EDs) in Korea between 1 January 2007 and 31 December 2014 were analyzed. The data were obtained from the National Emergency Department Information System (NEDIS) for children and adolescents under 18 years of age. The patients with diagnosis codes for CAP, based on International Classification of Disease, 10th revision diagnostic codes (Table 1) which was provided at the time of discharge from ED or after hospitalization were selected to identify eligible cases.
Categorical data was performed chi-square test, depending on age. Annual and seasonal distribution of ED visits were described by the number and % of total. The tau values were calculated using the Mann-Kendall method to analyze increasing or decreasing trends. Monthly incidence rate of diseases from data in 2008–2014 were decomposed and plotted into three components of trend, seasonality and remainder using LOESS procedure. Analyzes were performed using SAS ver. 9.4 (SAS Institute Inc., Cary, NC, USA), with a P value≤0.05 deemed significant.
Institutional Review Boards waived deliberation of this study.
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.
In summary, our results suggest that the clinical features correlated to different FLU viruses and to the relevant subtypes should be taken into consideration by health authorities to implement prevention strategies with the aim to reduce the number of sick subjects, the prevalence of hospitalization, and the circulation of FLU.
Indication for treatment includes all HBsAg-positive patients. Vaccination and the addition of hepatitis B immune globulin can be considered in this setting.
Antiviral treatment should be started with the beginning of IST. Tenofovir or entecavir are the drugs of choice. The treatment should be continued 1 year after withdrawal of IST, longer in recipients with cGVHD and patients exposed to depleting Ab.
No therapy of a CARV has been proven efficacious in controlled trials.
Ribavirin either given as inhalation or systemically has been suggested to reduce the risk for progression of upper respiratory tract RSV infection to LTD and possibly to reduce mortality in RSV pneumonia. No licensed therapy is available for any other CARV.
On admission, a nasopharyngeal swab was collected from children complaining of respiratory symptoms or fever without a focus. Samples were sent, as soon as possible, to the Department of Laboratory Medicine where a multiplex PCR test for respiratory viruses was conducted. The commercially available AdvanSure™ RV real-time PCR kit (LG Life Sciences Ltd., Seoul, Korea) was used to detect ADV, influenza A and B viruses, RSV, parainfluenza virus, rhinovirus, coronavirus, human metapneumovirus, and human bocavirus. A positive PCR result for ADV confirmed an ADV infection. If the PCR result was positive for only ADV, the child was assigned to the ADV group, and if the PCR result was positive for two or more viruses including ADV, the child was assigned to the coinfection group.
Upper respiratory tract infection (URTI) included acute pharyngitis, pharyngoconjunctival fever, and acute otitis media, while lower respiratory tract infection (LRTI) included acute bronchiolitis, acute bronchitis, and pneumonia.
A small number of studies have assessed the different therapeutic modalities that are reportedly beneficial in these patients. Adjustments in immunosuppressant therapy and the use of immunomodulating medications are potential therapeutic options. Adjustments in the immunosuppressive agents have demonstrated some positive outcomes. Cairn et al reported that the conversion of cyclosporine to tacrolimus stabilized spirometric measurements in patients with BOS while Whyte et al demonstrated similar results with the introduction of mycophenolate mofetil. In one study, BOS was less likely to progress when sirolimus was substituted for azathioprine in 37 lung transplant recipients receiving cyclosporine or tacrolimus, but the sirolimus had to be discontinued due to side effects.
The use of other immunosuppressant therapies in novel ways may improve outcomes for BOS. There is evolving research in the use of aerosolized cyclosporine. A single-center, randomized, double-blind, placebo-controlled trial of aerosolized cyclosporine was performed with initiation of the drug within six weeks after lung transplant along with routine systemic immunosuppression. Aerosolized cyclosporine did not improve the rate of acute rejection but improved survival and extended periods of chronic rejection-free survival. More recently, a single center randomized study demonstrated improvement in the pulmonary function of lung transplant patients who received aerosolized cyclosporine for the first 2 years after transplantation compared to placebo. A recent case report demonstrated that aerosolized tacrolimus was associated with improvement in both functional capacity and oxygenation in a patient with BOS. There are other therapies under investigation, including alemtuzumab, an anti-CD 52 antibody, which significantly improved the histological grade of BOS in 7 of 10 patients but had no impact on pulmonary function in an open label study.
The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Jilin University, China. Written informed consent was obtained from individual participants.
Respiratory failure due to infectious and non-infectious complications is common following HSCT and is associated with significant mortality, especially in those necessitating mechanical ventilation. Pulmonary complications are differentiated by key distinguishing features and their time-course following transplantation. In acutely ill patients meeting ARDS criteria, routine use of best-practice lung-protective strategies is recommended even once the underlying explanation for the respiratory failure is identified.
Pulmonary aspergillosis effects up to two-thirds of HSCT recipients, although incidence is declining with routine anti-Aspergillus prophylaxis during neutropenia and more effective treatment of graft-versus-host disease[42-44]. Pulmonary aspergillosis has been reported in upwards of 30% of HSCT recipients[3,42]. Risk factors include allogeneic transplant, unrelated donors, prolonged neutropenia, immunosuppressant use for graft-versus-host disease, and CMV infection[45-47]. Most common findings radiologically include pulmonary nodules with or without halo sign, ground glass opacities, and an air crescent sign from necrotic tissue in advanced cases[47-49]. Hemoptysis can be present and is typically associated with poor prognosis[50-52]. Diagnosis is confirmed by Aspergillus-specific PCR or Aspergillus sp. antigen in BAL[53,54]. Monotherapy with isavuconazole or voriconazole is the preferred first-line treatment and therapeutic drug monitoring should be utilized to ensure adequacy of dosing. Severe cases refractory to medical therapy or recurrent hemoptysis may be considered for surgical evaluation, though lung resection is highly morbid and associated with significant mortality in this population.
Incidence of Pneumocystis jirovecii pneumonia (PCP) has marginally declined in recent years as the use of prophylaxis has increased[57,58]. However, there is limited guidance and no consensus on which patients outside of HIV-positive individuals should receive prophylaxis, and therefore PCP remains highly relevant in HSCT recipients. Our institution routinely implements prophylaxis from engraftment until the first 100 d (or longer if patients are immunosuppressed for graft-versus host disease). PCP occurs late after HSCT and presents with acute onset severe respiratory failure[58-60]. Diagnosis is confirmed by the identification of Pneumocystis organisms in respiratory samples by PCR or fungal smear[58,61]. Sulfamethoxazole-trimethoprim is the treatment of choice and is highly effective in killing Pneumocystis sp. Patients with PCP typically die due to refractory hypoxemia from severe respiratory failure, and corticosteroids have failed to demonstrate benefit outside of the HIV population[62,63]. Nonetheless, adjunctive corticosteroids are typically administered in individuals with HSCT who develop PCP.
The mean age of the adult patients was 61.4 ± 16.6 years, and there was no difference according to sex (Table 1). Overall, 19 patients (17.3%) had viral co-infections, and 22 (20.0%) had bacterial co-infections. Co-infection did not affect event of ARDS, nosocomial infection and mortality. Most patients (n = 105, 95.5%) had comorbidities; these included diabetes, malignancy, pulmonary disease, cardiac disease, ESRD, and liver cirrhosis and they were being treated with corticosteroid or immunosuppressive medication. Almost patients had pneumonia on chest X-ray (93.6%), and 22 patients (20%) had ARDS (Table 1). Half of the patients with hMPV-associated ARDS had severe disease according to the Berlin definition. The in-hospital mortality rate was 10.9%, and the 1-year all-cause mortality rate was 15.5%. The patients with ARDS showed higher in-hospital (36.4%) and 1-year all-cause (40.9%) mortality rates than those without ARDS (Table 1). Forty-three patients were found to have nosocomial infections (39%) (Table 1). Regarding laboratory findings, lymphocytopenia (<1,500/mm3 ), high levels of CRP, BUN and creatinine, and low levels of albumin were observed (Table 2).