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Low-dose systemic corticosteroids may be used for septic shock related to severe influenza since evidence from RCTs suggests that corticosteroids may be associated with delayed clearance of viruses [21–23] and invasive fungal infections. Case control studies and a RCT suggested that plasma and hyperimmune globulin have demonstrated favorable responses in patients with severe avian influenza A (H5N1) and H1N1pdm09 infection compared with controls [27, 28, 198]. Further evaluation of novel treatments with RCTs is needed.
Two new neuraminidase inhibitors have recently been described: peramivir and laninamivir octanoate. Peramivir, which can be given as a single intravenous dose, was authorized for a short period by the US Food and Drug Administration (FDA) for emergent intravenous use in hospitalized patients with the 2009 H1N1 pandemic influenza virus. Laninamivir is given as a single inhaled dose for the treatment of seasonal influenza in adults and may also treat oseltamivir-resistant virus. In addition, new therapeutics for the treatment of influenza A virus infections are under development [13–15, 18, 28, 39, 50, 114–195]. In this regard, the drug, favipiravir (T-705) has been shown to inhibit a variety of influenza viruses, including highly pathogenic avian influenza H5N1 viruses. Finally, numerous antivirals such as entry inhibitors, nucleoside analogues such as cidofovir, viral enzyme inhibitors (such as terminase and helicase enzyme inhibitors), and translation inhibitors may be utilized in an off-label indication for treatment of viral infections [13, 113].
It has been recommended that treatment or prevention of a viral disease may be a superior method for diminishing of complications from influenza.84,85 Since viral infections might lead to secondary bacterial infection, it is prudent to vaccinate patients with the influenza vaccine to diminish the risk of OM in children and pneumonia in adults.62
It has also been published that live attenuated influenza vaccine is effective in reducing the incidence of all-cause AOM86–88 and pneumonia89 compared to placebo in children. In addition, the intranasal influenza vaccine can reduce OM by 44%.90 Moreover, studies have shown that a combined influenza/pneumococcal vaccine is efficient in the prevention of OM in children and pneumonia.91,92 However, the credit of protection was awarded to the influenza vaccine since studies have shown that pneumococcal vaccine has no benefit in the reduction of AOM.93,94 In addition, the pneumococcal polysaccharide vaccine showed no efficacy in the prevention of pneumonia in adults.95
Treatment of viral infection is anticipated to prevent bacterial superinfections. Currently, the only respiratory virus that is pharmacologically treatable is the influenza viruses (Type A and B).62 Neuraminidase inhibitors can potentially diminish the morbidity related to influenza.96 Oseltamivir can reduce the incidence of AOM in preschool children,97 and the reduction rate can be up to 44%.98 A meta-analysis review showed that oral oseltamivir reduces the rate of hospitalization by 25% and morbidity by 75%.99 In addition, its use can reduce the use of antibiotics by up to 50%,100,101 The same concept of protection applies to vaccines that prevent against RSV infections.62 The vaccine available for RSV is palivizumab (MedImmune, Gaithersburg, MD, USA), a humanized monoclonal antibody that perceives the fusion protein of RSV. The other monoclonal antibody that is under clinical trials is motavizumab (MedImmune), which has a higher affinity for RSV fusion protein than palivizumab and can prevent against medically attended lower respiratory tract infection.102
As shown in Table 4, 66 episodes (74.2%) recovered without pulmonary complications or intervention and 23 episodes (25.8%) developed complications. Prophylactic or therapeutic antibiotics were used in 78 episodes (87.6%). Oxygen was required in 21 episodes (23.6%). Pleural effusion was detected on chest radiograph in 15 episodes (16.9%). Mechanical ventilation in the intensive care unit was used in 11 episodes, and the mean duration of ventilator use was 18.4 days.
Among 89 clinical episodes which were developed in 58 HSCT patients, 3 patients died of respiratory failure directly related to respiratory viral infection. One patient who underwent bone marrow transplantation (BMT) for relapsed acute lymphocytic leukemia died of acute respiratory distress after an adenoviral infection. Another patient who underwent peripheral blood stem cell transplantation (PBSCT) for acute myeloplastic leukemia died of respiratory failure, again after an adenoviral infection. Immunosuppressive agents were discontinued as respiratory symptoms aggravated. Both patients were to receive treatment with Cidofovir 5 mg/kg weekly, but after 1 administered dose, they deceased. A third patient, who underwent PBSCT, was hospitalized for relapsed acute myelodysplastic leukemia. This patient had been suffering from chronic graft-versus-host disease (GVHD) and was being treated with prednisolone. A PIV-3 infection occurred during immunosuppressant treatment for GVHD. After PIV-3 was confirmed, her respiratory distress aggravated, eventually leading to death.
Antibiotics were given to all of the patients empirically before and after confirmed diagnosis. There is currently no formally approved antiviral therapy for the treatment of severe life-threatening adenovirus infection in China. Acyclovir, ganciclovir or ribavirin is commonly chosen by the physician to treat adenoviral infection. In this study, all of the fatal patients were administered antiviral drugs—one was treated with ganciclovir, two with acyclovir and one with ribavirin. In surviving patients, 50% were treated with antiviral drugs—three with ganciclovir, one with acyclovir and one with ribavirin. All of the fatal patients (4/4) were complicated with ARDS and admitted to the ICU. They needed mechanical ventilation, and three of them received ECMO to maintain oxygenation. For surviving patients, one of them (1/10) was admitted to the ICU due to ARDS, and had mechanical ventilation and ECMO; one patient with respiratory failure was treated with non-invasive ventilation, and one patient was treated for myocarditis. The myocarditis patient presented with peak levels of creatine kinase isoenzyme (CK-MB) and cardiac troponin I (CTNI) on day 7–8 after disease onset, and eight days later, with viral load going down to negative, CK-MB and CTNI went down to normal levels in parallel (Fig 4).
For the four fatal patients, the times of death were on days 14, 16, 22 and 28 after disease onset, respectively. There was no significant difference in length of stay in-hospital between the two groups (13.5±6.5 days vs 13.3±9.2 days, p = 0.969) (Table 2).
The rate of concurrent serious bacterial infections with viral illness is appreciable. Similar emphasis must be given to the prevention and treatment of viral illnesses, especially in young children. Furthermore, health care providers should emphasize to parents on the importance of clinical follow-up of infants and young children diagnosed with VRTI. Moreover, the introduction of MxA in the diagnosis of viral illnesses in children is promising.
The detection of a viral pathogen led to changes in the management of the disease in 23 (33.3%) patients. Twelve patients received antiviral therapy such as oseltamivir and ribavirin, and empirical antiviral therapy was continued or extended in 4 patients. The use of immunosuppressive agents, including steroids, was decreased or stopped in 3 patients. In some patients, antibiotics (n = 2) or antiviral agents (n = 1) were discontinued because bacterial pathogen was no longer suspected, or the detected virus had no effective antiviral agent (Table 4).
The clinical outcomes, such as the length of hospital stay, length of ICU stay, and in-hospital mortality, were compared according to changes in management. However, the differences were not statistically significant (S2 Table).
Before admission, 31 of the 53 patients with viral pneumonia had received antibiotics. Eleven patients showed early treatment failure with a worsened condition. The other 20 patients showed both early and late treatment failure. Two of these 20 patients received effective corticosteroid therapy before admission. The condition of the other 18 patients became worse after antibiotic treatment. The remaining 22 patients had not received antibiotics or corticosteroids before admission, but they were referred to our hospital after their condition worsened. None of these patients had received neuraminidase inhibitors (NIs) before admission.
After admission, 46 of these 53 patients received antibiotics with β-lactams plus macrolides (n=22, 41.5%), fluoroquinolones with or without other antibiotics (n=16, 30.2%), and others (n=8, 15.1%). Antibiotics were not administered to 7 patients after admission because antibiotic treatment administered by their local physicians had failed.
Six of 13 patients with influenza-associated pneumonia received NIs (from the 5th to 23rd day from the onset of initial symptoms). In three of these 6 patients, both NIs and corticosteroids were started simultaneously, and these patients improved. In 4 of the 6 patients, NIs were started without corticosteroids (from the 5th, 8th, and 11th day after the onset of symptoms). NIs were effective in 2 of 3 patients. In the other patient, however, NI was administered from the 11th day after onset, but the patient showed early treatment failure and was switched to corticosteroid therapy from the 14th day, which was effective. In 7 patients who did not receive NIs, 6 received corticosteroid therapy (which was effective) from the 11th, 19th, 22nd, 23rd, 25th, and 47th day, respectively, after the onset of symptoms. The pulmonary shadows of the two other patients who did not receive corticosteroids or NIs improved spontaneously during follow-up. Among the 40 patients suffering from viral pneumonia due to non-influenza viruses, corticosteroids with antibiotics were administered to 21 patients from a median of 15 (range, 6-45) days after the onset of symptoms. Two of these patients died. Corticosteroid therapy was effective in one of these patients; however, this patient experienced repeated episodes of aspiration pneumonia causing their condition to deteriorate until their death. The other patient showed early and late treatment failure with corticosteroid therapy, causing the progressive deterioration of the patient's condition until their death. The other 19 patients received antibiotics without corticosteroids and all survived.
The physician suspected the patient of having atypical pathogens when they had persistent or deteriorating symptoms or signs despite treatment with appropriate empirical antibiotics for 2–3 days. Thus, we compared the clinicolaboratory findings between Adv and Non-Adv group patients who were unresponsive to the initial antibiotics treatment (Table 4). The number of patients who did not a response to initial antibiotics treatment was 47 and 50 in the Adv and Non-Adv groups, respectively. The percentage of patients having leukocytosis and monocytopenia was higher in the Adv patients, although there was no significant difference in white blood cell and platelet counts between the two groups. Leukopenia and thrombocytopenia, which were a showed a significant difference in all study patients, showed no difference in patients with unresponsiveness to initial antibiotics treatment (P = 0.720, P = 0.733, respectively).
A greater number of Adv group patients exhibited no response to antipyretic treatment compared with the Non-Adv group patients (25.5% vs. 10.0%, P = 0.045) as well as the number of patients to reach over 40 °C and 39 to 40 °C (P = 0.003). In addition, the Adv group patients had a higher mean temperature at admission than the Non-Adv group patients (37.8 ± 0.3 vs. 37.3 ± 0.2, P = 0.005).
Table 5 compares the clinicolaboratory variables between the combined Adv (cAdv), Non-Adv, and only Adv identified pathogen (OAIP) group patients. Compared to the cAdv and Non-Adv patients, more patients in the OAIP group exhibited the following characteristics: were currently smoking; had leukopenia, lymphopenia, monocytopenia, and thrombocytopenia; exhibited a longer duration of fever after symptom onset; had a higher maximal temperature at admission (over 40 °C and 39–40 °C); and exhibited no response to antipyretics at admission.
All patients received empirical antibiotic treatment (Table 6) as follows: a 3rd generation cephalosporin plus azithromycin was the most common regimen (n = 243, 96.8%), followed by piperacillin/tazobactam plus respiratory quinolone (n = 5, 2.0%). The change in antibiotics treatment regimen was more frequent in the Adv group patients than in the Non-Adv patients (70.1% vs. 27.2%, P = 0.024). The duration of antibiotic treatment was not significantly different between the two groups. In our study, we did not evaluate the administration of cidofovir or adjuvant intravenous immunoglobulin (IVIG). In addition, there were no patients who received mechanical ventilation or extracorporeal membrane oxygenation support.
At admission, the mean dose of antipyretics administered was higher in the Adv group patients than in the Non-Adv group patients (5.52 vs. 4.30 g, P = 0.032), although the overall duration of antipyretics was not significantly different between the two groups. In this study, we identified adverse events after antipyretics administration, such as hypotension, gastrointestinal trouble, skin rash, and elevated liver enzyme, which were commonly observed in the Adv group patients (P = 0.005).
The time to overall clinical stabilization from admission was significantly longer in the Adv group patients than in the Non-Adv group patients (4.3 ± 2.8 d vs. 2.9 ± 1.8 d, P = 0.034). In addition, the length of hospital was not significantly different between the two groups, and no patient died in our study.
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.
We obtained written informed consent from a parent or a caregiver of the participating children before enrolling them into the study. The study protocol was reviewed and approved by the institutional review boards (IRB; named as Research Review Committee and Ethical Review Committee) of icddr,b. CDC relied on icddr,b’s IRB review.
This is the second hMPV pneumonia in a kidney-transplanted recipient described in the literature. The first reported case was a severe LRI requiring transient intensive care unit stay. It occurred three years after kidney transplantation, while receiving immunosuppressive regimen consisting of ciclosporine (125 mg b.i.d), azathioprine (75 mg/d), and prednisone (10 mg/d). Compared to this case, our patient had mild symptoms, mainly cough and upper respiratory symptoms. He was also less immunosuppressed without corticosteroids regimen.
In solid organ transplanted patients, hMPV is responsible for LRI and may lead to hospitalization and significant respiratory illness in up to 63% of cases [6, 8]. As initial clinical symptoms are nonspecific, thoracic CT scan can be more helpful than chest X-ray, which is less sensitive. Consolidation, nodular infiltrates, and pleural effusions may be seen. Subpleural and basal areas are usually observed, and bilateral locations are seen in 50% of cases, as in our case. Whereas crazy paving, network of a smooth linear pattern superimposed on an area of ground-glass opacity, is unusual, bronchiectasis is common, up to 68% in the series by Wong et al..
Of note, lymphopenia, as noticed in our patient, is the most common feature reported in HSCT patients with hMPV, accounting for 73% of patients in one series. This illustrates that although innate immune responses are stimulated upon hMPV exposure, adaptive immunity also appears important to control hMPV. As for other paramyxoviruses, the matrix proteins are involved in the induction of proinflammatory and Th1 responses by dendritic cells and macrophages (i.e., production of interleukin-2 and interferon-γ). Inflammation may cause diffuse alveolar damage and hyaline membrane formation as shown by histopathology investigations.
Apart from other respiratory viral infections occurring in SOT recipients, differential diagnoses of hMPV-associated LRI include severe bacterial and fungal pneumonitis, particularly Pneumocystis pneumonia. Ribavirin, previously shown active in a mouse model of infection, has been suggested as a potential antiviral therapy in HSCT and lung transplant recipients with hMPV-associated LRI [14, 15]. In our case and in the other case of the literature, ribavirin was not used because the diagnosis was made retrospectively after the patient's spontaneous clinical improvement.
In conclusion, hMPV has to be considered as a potential cause of LRI in kidney transplant recipients and may mimic Pneumocystis pneumonia. A prompt recognition would have avoided antibiotic use and further diagnostic studies such as bronchoscopy. Its early detection using immunofluorescence and/or RT-PCR must be proposed routinely in transplantation settings. In addition, early recognition could improve the implementation of appropriate infection control practices to prevent viral spread of this potential life-threatening infection in immunocompromised patients.
The primary endpoint evaluated was in-hospital mortality. Secondary endpoints included hospital length-of-stay (LOS), intensive care unit (ICU) admission, and readmission rates at 30, 90, and 180 days after the index hospitalization.
Our study identified the risk factors, prevalence, and clinical impact of virus detection among patients with severe pneumonia who were admitted to the medical ICU. Respiratory viral infection should be suspected in patients from the community, during the winter season, in patients with recent chemotherapy, and in patients with a low serum platelet count. The overall virus detection rate was 13.3%, with RSV A being the most common pathogen and influenza A virus being the most common pathogen of bacterial coinfection. Such detection of respiratory viruses led to changes in management in one-third of the patients.
The virus detection rate was higher in February and January as well as in patients with a community onset. This finding supports the recommendation to use empirical therapy against influenza virus during the winter season for hospitalized CAP patients. Patients with recent chemotherapy were at a higher risk for viral pneumonia, which is consistent with previous knowledge that immunosuppression is a risk factor for influenza viral pneumonia. The virus detection rate was highest in patients who had undergone both invasive and noninvasive sampling (n = 25), and more information was obtained from further invasive sampling in approximately 28% of the patients (n = 7). Although the potential harm of BAL in critically ill patients must be thoroughly reviewed before the procedure, further invasive samplings should be considered in selected patients stated above (winter seasons, community onset, recent chemotherapy, low platelet count, and so on) for additional virus detection.
RSV, an important pathogen that can result in severe pneumonia, especially in the elderly, was the most common pathogen detected. Previous studies have differed in the detailed distribution of pathogens, but many have reported that the most common viral pathogens include influenza, parainfluenza, and RSV [21–23]. Considering the limited strategies for treating and preventing respiratory viruses other than influenza, this distribution of various pathogens may further emphasize the need for the development of novel antiviral agents and vaccines.
This study is the first to specify the clinical impact of adult-onset severe viral pneumonia according to the detection of respiratory viruses. Previous studies have been conducted in children or with milder forms of pneumonia. However, children have much higher rates of respiratory viral illnesses than adults and should be discussed separately, and severe pneumonia is of most interest in the ICU setting [6, 25]. Among the 23 patients whose management was changed, the most common change was in antiviral agents (n = 18). Currently, anti-influenza agents are the only actively used antiviral agents, and ribavirin is the only antiviral treatment option for non-influenza respiratory viruses. Our study results emphasize the need for the development of novel antiviral agents against respiratory viruses. Apart from antiviral agents, respiratory viral detection in critically ill patients led to a reduction or cessation of immunosuppressant treatment in 3 patients. The use of high-dose steroids is known to be associated with a higher mortality rate and longer viral shedding in influenza A patients. Therefore, it can be helpful to reduce the use of immune-modulating agents, including steroids, to improve patient outcomes. Two other patients stopped using empirical antibiotics, and their treatment focused on the respiratory viruses as pathogens. The long-term use of antibacterial agents in patients with viral pneumonia is known to increase the risk for developing multidrug-resistant pathogens and Clostridium difficile infection rather than improving clinical outcomes [28, 29].
The bacterial coinfection rate of the present study was similar to that of previous reports [8, 30], which further supports the fact that patients with viral infection should be carefully examined for any additional bacterial infection. The most common bacterial pathogens of coinfection were common colonizers of the nasopharynx. However, we failed to show a significant difference in mortality related to coinfection. This result is also consistent with previous reports, which showed comparable results for patients with and without bacterial coinfection. The consequences of bacterial coinfection require further study.
Our study has several limitations. First, it was a retrospective study performed in a single center. Second, we considered all detected microorganisms as pathogens. However, a detected respiratory virus was unlikely to be neutral and was pathogenic in certain group of patients according to a previous report. Although further studies are required, the possibility of invasiveness of detected respiratory virus should be taken into account. Third, although the RT-PCR kit of our institution is known to have good sensitivity and specificity [12–14], the risk of false-negativity cannot be perfectly ruled out. Fourth, the detection rate was lower than that of previous reports [21, 22]. The limited number of reported pathogens and inclusion of HAP may be responsible for this result. Of the 519 patients who underwent multiplex RT-PCR detection of respiratory viral pathogens, 188 (36.2%) were HAP patients. The detection rate increased to 18.8% when only CAP patients were considered, which is comparable to the results from a recent systematic review.
In conclusion, non-influenza respiratory viruses were commonly detected in severe pneumonia patients, and the detection of viral pathogens in patients with severe pneumonia can lead to changes in clinical management strategies. Therefore, RT-PCR analysis should be actively performed for severe pneumonia in the ICU, especially among those with risk factors for viral infection. Furthermore, future efforts are required to develop novel antiviral agents for non-influenza respiratory viruses.
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Our two case reports suggest that patients with H1N1 should be screened for Legionella, which is not currently common practice. This is particularly important since the signs and symptoms of both infections are similar. Doctors should never be dazzled by contingency and media sensationalism in decision making. With prompt identification of the bacterial etiology of pneumonia, appropriate treatment can be started with both antibacterial therapy and antiviral medications. The length of hospital stay and the mortality of both pandemic and seasonal influenza can be reduced.
This study illustrated that respiratory viral infections are common among children who have undergone HSCT. In our study, respiratory viruses were identified in 27.9% of respiratory samples. Rhinovirus was the most common virus (28.1%), PIV-3 was second (18.0%), and RSV-A was third (14.6%). Lower respiratory tract infections were diagnosed in 38.2% and hospital-acquired infection episodes were in 63.0%. Many recent studies have reported that community respiratory viruses, particularly RSV and PIV, are significant causes of morbidity and mortality among HSCT recipients (15, 16). However, the study for respiratory viral infection of previously healthy children in similar area revealed different results that RSV (23.7%) was the most common detected virus, and as followed adenovirus (6.8%), PIV-3 (6.2%), rhinovirus (5.8%), and hMPV (4.7%) (17). Relatively low prevalence of rhinovirus and human coronavirus (2.9%) implied that the differences exist between healthy population and children who have undergone HSCT.
A review of cases of nonbacterial pneumonia among HSCT recipients from 1969 to 1979 did not report any community-acquired respiratory viral infections (18). However, the prevalence of respiratory viral infections after HSCT has been increasingly reported ranging from 16.5% to 38% (7, 19, 20). In our study, respiratory viruses were detected in 58 (33.1%) HSCT patients.
The prevalence of respiratory viral infections among HSCT patients depends on the diagnostic method used. We used real time RT-PCR method because of recent common usage and excellent sensitivity in comparison with conventional methods such as viral culture and immunofluorescent stain of viral antigen. The reported frequency of RSV infections has varied from 35% to 49%; influenza virus infections from 11% to 45%; PIV infections from 8% to 30%; and rhinovirus infections from 4% to 9% (15, 21). This study demonstrated that rhinovirus was the most frequently detected infection. However, the diagnostic technologies used in each study were different. Therefore, the results of our study cannot be directly compared with those of other studies. A prospective study using RT-PCR shows that rhinovirus was the most common isolate (37.0%) in HSCT patients (22).
Similar to community epidemiology, PIV-3 is common from June to September and RSV is common from December to March. These results were not significantly different from most studies (20, 23).
One of the important findings from this study is that the great proportion (63.0%) of respiratory viral infections was acquired while HSCT patients were hospitalized. High nosocomial infection rates remind us of the importance of contact or droplet precautions and visitor limitation. In most cases, specific antiviral agents are difficult to use clinically, so prevention is the most useful method to reduce respiratory viral infection.
Clinically, URI is the most common predominant presentation of respiratory viral infection and usually resolves without therapy. In our study, 61.8% of respiratory viral infections were limited to URI and 38.2% of those progressed to LRTI. In a European study, 55% of total respiratory viral infection was reported as LRTI (15). A prospective study in adults with HSCT or hematologic malignancy reported that during the follow-up period, 18% of patients had pneumonia or had progression to pneumonia (23). Lymphopenia (≤ 200 cells/µL) was known to be a risk factor for progression to LRTI (21). But in our study, lymphopenia was not significant to the progression to LRTI.
In this study, we found three fatal cases among 89 clinical episodes which were developed in 58 HSCT patients. In these fatal cases, basal lung condition of patients was poor when respiratory distress occurred. However, respiratory viral infection triggered respiratory dysfunction, and their death was probably related to respiratory viral infection. Many other studies reported various mortality and fatality. RSV related mortality in children treated for acute myeloid leukemia was 10% (24), and one report demonstrated PIV-associated fatality of 27% among HSCT recipients (25). Other studies reported mortality rates from respiratory viral infections among HSCT recipients of 0.5% and 0.6% (15, 20).
There are few antiviral therapeutic options against respiratory viruses except influenza virus in HSCT patients. Neuramidase inhibitors, oseltamivir and zanamivir, are known to resolve influenza symptoms in immunocompromised patients (26). M2 inhibitors, amantadine and rimantadine, have been used in some centers, but are limited to influenza A and have many side effects including antiviral resistance (27). The primary therapy for RSV that has been the best studied is aerosolized ribavirin. However, similar to other viral agents, its use has the problem of cost-effectiveness. Researchers reported that aerosolized ribavirin resulted in a decrease in viral load but no difference in the progression to pneumonia (28). Aerosolized and oral ribavirin are used for therapy of PIV infection in transplant recipients with conflicting results (29, 30). Various treatments for adenovirus have been tried including high-dose intravenous immunoglobulin, ribavirin and cidofovir. However, the clinical efficacy of these agents remains unclear. These therapeutic limitations emphasize importance of the prevention strategy and strict infection control program in the hospital.
This study included a relatively large number of patients enrolled at one center. However, our retrospective study dependent on medical records has some limitations for clinical evaluation. In particular, risk factors or prognosis for respiratory viral infection such as conditioning regimen, presence of graft-versus-host disease, taking history of immunosuppressant agents, and separation principle of hospitalized patients cannot be investigated. Despite these limitations, this study is meaningful considering aspects that show the common prevalence of respiratory viral infection in HSCT children. This effort aids investigation of the clinical features and epidemiologic character of virus infections in this patient population.
This study has demonstrated that respiratory viral infection is relatively high in HSCT patients and more than half of the respiratory infections were acquired during hospitalization. These findings emphasize importance of the preventive strategies against respiratory viral infection in HSCT patients at high risk.
NPA sample (200 μl) from the patient was subjected to total nucleic extraction after addition of internal control bacteriophage MS2 (20 μl) using the MagNA Pure LC Total Nucleic Acid Isolation kit (Roche Diagnostics, Germany) on Magna Pure LC 2.0 platform, following the manufacturer's instructions. The method is based on magnetic-bead technology. The procedure included cellular destruction, nucleic acid binding on beads, and washing steps to remove cellular and purified nucleic acid elution. Extracted nucleic acids were eluted in 50 µl of elution buffer and stored at −80°C for RVP FAST assay.
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We investigated the relationship between the virological factors and clinical outcomes in a cohort of 14 hospitalized adults with AdV pneumonia. Our results suggest that a higher initial viral load (108 copy/ml) in the respiratory tract samples on day 5–7 after disease onset is a predictor for fatal clinical outcome. We also reported that viremia is common and sustained viremia for 14 days or more may be associated with mortality
The pathogenesis of mortality in Adv pneumonia is still unknown. Virological factors, e.g., a new strain with new genetics, viral load, slow virus clearance and systemic infection with viremia likely play key roles for severe Adv [2–8]. However, no study has evaluated the viral shedding history among immunocompetent adults with AdV pneumonia. This study first monitored the consecutive viral load in respiratory tract samples and whole blood samples. Our previous clinical study demonstrated that on day 5–7 after disease onset, the peak stage of illness presented for patients with shortness of breath or severe dyspnea. Again, in this study, we showed that the viral load on day 5–7 could also provide an insight into the severity of illness. Evidence even proved that a higher level of viral load in respiratory tract samples on day 5–7 after disease onset was significantly associated with fatal outcome.
We have noted that viremia is quite common on day 5–7 after disease onset, when 9 out of 11 (81.8%) patients had viremia. Adenovirus viremia has been found in hematopoietic stem cell transplantation recipients and associated with AdV disease. Compared with previous reports of viremia and clinical outcomes, another novel finding is that we demonstrated that fatal outcomes could be predicted by sustained viremia, but not by viremia itself. In this study, we showed that 100% (4/4) of patients in fatal cases presented with viremia on day 12–14 after disease onset, compared with 60% (p = 0.126) of the patients in surviving cases.
In one case, as shown in Fig 2, even though the patient presented with a higher viral load (108.32 copies / ml) in tracheal aspiration, which may be associated fatal outcome, his clinical manifestation recovered gradually with a downward trend in the viral load in respiratory tract and whole blood samples. Compared to this case in Fig 3, the patient described in Fig 3 not only had a higher viral load (109.25 copies/ml) in tracheal aspiration but also presented with sustained elevated viral copies, especially in whole blood. Shike et al. also reported a 6-month-old infant with systemic infection by adenovirus who had high-level viremia and showed reduction in viral load paralleling her clinical recovery. Therefore, in severe cases, dynamic monitoring of viral shedding, especially in whole blood, could help predict the clinical outcome. Patients might have bad outcomes if the viral load in whole blood does not present a significant downward trend around two weeks after disease onset.
There is currently no formally approved antiviral therapy for the treatment of severe life-threatening adenovirus infection in China. Cidofovir is considered the medicine of choice for severe infection in immunocompromised patients. Cidofovir is not available in most hospitals in China, including our hospital. Acyclovir, ganciclovir or ribavirin is usually prescribed in China. In this study, antiviral drugs were administered in all of the fatal cases—one patient was treated with ganciclovir, two with acyclovir and one with ribavirin. In surviving patients, 50% were treated by antiviral drugs—three with ganciclovir, one with acyclovir and one with ribavirin. The choice of the antiviral medicine was decided by the patient’s physician. As none of these three medicines have been confirmed to be effective for AdV infection, the relationship between viral shedding and clinical outcomes in this study was not associated with anti-adenoviral treatment effect.
Our study has two limitations. As AdV 55 was the most common infection type (10/14, 71.4%) in this study, results might be more significant in AdV 55-associated pneumonia and might not be generalizable to other types of AdV pneumonia. In our previous study, adults infected with AdV 55 were 10 years older and presented with higher PSI scores compared with adults infected with other serotypes. Another limitation of this descriptive work may be the small number of analyzed patients, especially in the group of fatal cases (n = 4). More cases are needed to confirm our findings.
In conclusion, our data provide new insight into the virology of AdV pneumonia. A higher initial viral load (108 copy/ml) in the respiratory tract on day 5–7 after disease onset and sustained viremia for 2 weeks or more may be associated with fatal clinical outcomes.
This study was conducted between January 2015 and January 2016 at the Albert Royer Paediatric hospital, the Roi Baudouin Hospital, and the Abass Ndao Hospital, all located in Dakar, Senegal. Inclusion criteria were as follows: children aged under 5 years attending with an upper or lower airway infection.
Bronchoalveolar lavage, sinus fluids, and throat swab samples were collected and referred to the biotechnology unit of the laboratory of bacteriology and virology of Aristide Le Dantec and to the virology unit of Pasteur Institute.
This study has been approved by the Ethics Committee for Research of the Cheikh Anta DIOP University of Dakar. Samples and information for questionnaires have been collected after patient’s informed consent.
The main 9-valent pneumococcal conjugated vaccine (PCV9) efficacy trial and subsequent retrospective analysis of study participants were approved by the Human Research Ethics Committee (Medical) of the University of the Witwatersrand. The main study did not have a clinical trials number since it was undertaken prior to registration of clinical trials having been made mandatory. Signed informed consent was obtained from the parent/legal guardians of all the study participants as part of the main trial. The Ethics Committee did not require additional consent for this study.
For patient descriptions, we compared RSV-positive with RSV-negative patients within two groups of patients: all ARI patients and ARI patients with pneumonia. For the assessment of predictive factors for severity, patients with severe outcomes were compared with patients with no severe outcome within 6 groups of patients: all ARI patients, RSV-positive ARI patients, RSV-negative ARI patients, and those same three groups in patients less than 2-year old. Death, stay in ICU, oxygen use and severe pneumoniae were considered as indicators for severity. However, the mortality rate was too low to be analyzed and the analyses of ICU stay and oxygen use did not provide any added-value, so ultimately severe pneumonia alone was analyzed as an indicator of severe outcome. Data were double entered into an Access database (Microsoft Corporation). Statistical analysis was performed using Statistical Package for the Social Sciences version 23.0 for Windows (SPSS Inc., Chicago, IL, USA). For comparison of categorical data, the Pearson Chi-square (χ2) test and Fisher’s exact test were used as appropriate. The ANOVA test was applied to compare continuous variables. We fitted a binary logistic regression model, including a stepwise selection procedure, to assess predictive factors for severity. The level of significance was set at p < 0.05.