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Except for HIV, hepatitis C and hepatitis B, combination drug therapies are not established for other viruses, such as HSV and influenza. Triple and dual drug combinations may be synergistic in their antiviral action. The efficacy of oseltamivir-zanamivir combinations for seasonal influenza was established in a randomized controlled clinical study. However, clinical antagonism between oseltamivir and zanamivir was suggested in another study [188, 193].
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.
Empiric use of antibiotics remains as cornerstone of treating pneumonia in the absence of effective point-of-care diagnostics for differentiating bacterial from viral infection. Many children who have viral pneumonia will continue to receive antibiotics without benefit. Early reliable detection of viral pneumonia, or early exclusion of bacterial pneumonia, could reduce unnecessary antibiotic therapy, thereby mitigating the risk of emerging antibiotic resistance. While we have been unable to identify a single biomarker or clinical feature that could be used to confidently distinguish bacterial from viral pneumonia, our findings suggest there may be utility in more sophisticated algorithms that integrate a number of clinical, microbiological, inflammatory biomarker, or radiological factors to improve pneumonia diagnostics and better targeting therapies.
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.
Knowing which patients with LRTIs to treat and not to treat is challenging to determine, and physicians often err on the side of caution and prescribe antibiotics, given the high mortality rates of some bacterial LRTIs often without diagnostic results. Most patients are then empirically treated with antibiotics to pre-emptively avoid severe complications from bacterial LRTIs.
Improved diagnosis of the etiology of these infections would enable targeted therapy, leading to an overall more judicious use of antibiotics, which would likely decrease the rate of antimicrobial drug resistance as well as the safety impact of inappropriate treatment modalities on the patient. Due to the improper treatment of LRTIs, some infected patients may not be treated adequately because the responsible bacterium (such as S. pneumoniae, methicillin-resistant S. aureus and Gram-negative bacilli) is resistant to available antibiotics, leaving physicians without a weapon to combat the illness. The prudent use of available antibiotics in patients and animals, giving them only when needed, with the correct diagnosis and etiologic understanding, and in the correct dosage, dose intervals and duration is imperative. Antimicrobial stewardship is based on this premise. Over 262 million courses of outpatient antibiotic therapy were prescribed in 2011 with half of those antibiotics being unnecessary. The most inappropriate use is for acute respiratory infections, including acute bronchitis. Further research into rapid, patient-friendly, inexpensive, and accessible diagnostic modalities to appropriately characterize LRTIs as bacterial versus viral versus other is necessary to harness antibiotic use. In addition, determination of the causative bacterial pathogen will further antibiotic stewardship programs, lowering the risk of propagating resistance and unwanted adverse events including the development of C. difficile. The advancements noted above are certainly moving in the right direction to understanding the etiology of pneumonia in a rapid manner, but development still continues for even faster, more comprehensive testing.
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).
The pre-publication history for this paper can be accessed here:
The pre-publication history for this paper can be accessed here:
The management of complicated pneumonia in pediatric patients is an area of controversy. Different approaches are generally categorized as conservative, involving the use of antibiotics alone versus procedural interventions to drain the pleural space, as performed in our case. Antibiotics are a critical component in medical management for parapneumonic effusion and empyema. Regimens are guided by local policies surrounding susceptibility patterns focusing on the current, increased resistance of S. pneumoniae and MRSA to penicillin. As seen in our case, it is crucial to always attempt to obtain blood cultures prior to initiation of antibiotics. In absence of confirmed organism by culture, studies suggest empiric coverage with ceftriaxone or cefotaxime. Some experts suggest the addition of clindamycin for broader coverage of anaerobic or MRSA coverage, with the substitution of vancomycin for clindamycin for suspected MRSA pneumonia. Antibiotics would be switched to oral once drainage is complete and patient improves without oxygen, generally three to four weeks in duration given the absence of additional complications.
Corticosteroids could increase mortality in patients with influenza pneumonia. Randomized controlled studies are needed to further verify this conclusion.
Infection control aspects of MERS have to do with preventing MERS exposures and minimizing person-to-person spread. Patients particularly from countries near the Arabian Peninsula who have an influenza-like illness should avoid travel until they are well. The following are based on CDC recommendations. If any patient has been exposed to a potential or known MERS case travel should be avoided. Household or family members exposed to potential or actual MERS cases should use masks. Such household and family members, while ill, if a family household member develops an ILI they should avoid public transportation, school, and work while ill. The individuals who are at increased risk for MERS include recent travelers from the Arabian Peninsula, particularly if such travelers develop fever and an ILI, including cough and shortness of breath, within 14 d after traveling from countries in or near the Arabian Peninsula. Those that have had close contact with someone that has recently traveled with respiratory symptoms and fever from countries in or near the Arabian Peninsula should be observed for 14 d starting from the day the patient was last exposed to the person.20 Those with increased risk for MERS also include those with close contact with a probable or confirmed case of MERS. Care should be taken with the exposed individual to monitor fever, cough, shortness of breath, and other symptoms, i.e., chills, myalgias, sore throat, nausea, vomiting, or diarrhea for 14 d counting from the last day of exposure to the ill contact. Healthcare personnel not utilizing proper infection control precautions are at increased risk for MERS.23,24 Close contact may be defined as any person that provides care for a patient, including healthcare workers, family members, or someone who had similarly close physical contact or any person who stayed at the same place, lived with, or visited the patient when the patient was ill.21-23 Infection control contact, and airborne precautions should be used while in close contact with symptomatic individuals or patients with MERS in the differential diagnosis.25 Infection control precautions should be observed when obtaining or conducting respiratory specimen testing for MERS. To prevent transmission to household members, masks should be worn in the house. Since person-to-person transmission has been demonstrated with MERS the use of masks and handwashing are important interventions to reduce transmission.
It has been shown that healthcare workers in contact with or taking care of MERS patients are at particularly high risk for developing MERS.23,26,27 Contact and airborne precautions should be used with appropriate personal protective devices to minimize the exposure of healthcare workers to suspected or known hospitalized MERS cases.26 Since it is not known how long MERS-CoV is present in respiratory secretions, it seems prudent that MERS patients remain on contact and airborne precautions until discharged.
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.
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.
The pre-publication history for this paper can be accessed here:
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.
This study highlights the potential benefits of improved diagnostics for respiratory viruses, primarily the potential for decreased antibacterial exposure and thus decreased selective pressure for resistant bacterial isolates. Antibacterial exposure applies selective pressure and promotes colonization/infection by resistant organisms including MRSA and VRE [40, 41]. Halting this process is essential to maintain effective therapeutic options in the future and may be aided by discontinuation of antibacterials in cases of viral pneumonia. In our study, patients with viral pneumonia exposed to long-course antibacterials had more occurrences of subsequent infection or colonization with MDRO isolates. In contrast, the number of patients with subsequent MDRO infection or colonization was not different between groups although this may be due to the small number of patients in each group. No differences in clinical outcomes, including in-hospital mortality and readmission rates, were observed between patient groups. In the setting of viral pneumonia and no coinfecting bacterial pathogens, discontinuation of antibacterials is reasonable in many if not most cases, and may allow for decreased overall antibacterial use. Enhanced diagnostic technologies can potentially be incorporated into antimicrobial stewardship practices to allow for de-escalation of unnecessary antibacterials. These findings warrant further investigation to determine the applicability of an antibacterial de-escalation approach in the setting of viral pneumonia.
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.
Case management of pneumonia is a strategy by which severity of disease is classified as severe or non-severe. All children receive early, appropriate oral antibiotics, and severe cases are referred for parenteral antibiotics. When implemented in high-burden areas before the availability of conjugate vaccines, case management as part of Integrated Management of Childhood Illness was associated with a 27% decrease in overall child mortality, and 42% decrease in pneumonia-specific mortality. However the predominance of viral causes of pneumonia and low case fatality have prompted concern about overuse of antibiotics. Several randomized controlled trials comparing oral antibiotics to placebo for non-severe pneumonia have been performed [75–77] and others are ongoing. In two studies, performed in Denmark and in India, outcomes of antibiotic and placebo treatments were equivalent [76, 77]. In the third study, in Pakistan, there was a non-significant 24% vs. 20% rate of failure in the placebo group, which was deemed to be non-equivalent to the antibiotic group. Furthermore, because WHO-classified non-severe pneumonia and bronchiolitis might be considered within a spectrum of lower respiratory disease, many children with clinical pneumonia could actually have viral bronchiolitis, for which antibiotics are not beneficial. This has been reflected in British and Spanish national pneumonia guidelines, which do not recommend routine antibiotic treatment for children younger than 2 years with evidence of pneumococcal conjugate vaccination who present with non-severe pneumonia. The United States’ national guidelines recommend withholding antibiotics in children up to age 5 years presenting with non-severe pneumonia. However, given the high mortality from pneumonia in low- and middle-income countries, the lack of easy access to care, and the high prevalence of risk factors for severe disease, revised World Health Organization pneumonia guidelines still recommend antibiotic treatment for all children who meet the WHO pneumonia case definitions.
Use of supplemental oxygen is life-saving, but this is not universally available in low- and middle-income countries; it is estimated that use of supplemental oxygen systems could reduce mortality of children with hypoxic pneumonia by 20%. Identifying systems capacity to increase availability of oxygen in health facilities, and identifying barriers to further implementation are among the top 15 priorities for future childhood pneumonia research. However, up to 81% of pneumonia deaths in 2010 occurred outside health facilities, so there are major challenges with access to health services and health-seeking behavior of vulnerable populations. Identifying and changing the barriers to accessing health care is an important area with the potential to impact the survival and health of the most vulnerable children.
The pre-publication history for this paper can be accessed here:
Various procedural interventions are available for pediatric patients with empyema such as small bore percutaneous chest tube placement (with or without fibrinolytics), thoracentesis, video-assisted thoracoscopic surgery (VATS), and open thoracotomy with decortication. Initially, diagnosis and the decision to drain a pediatric patient with pleural effusion were based on the staging of pleural infection via thoracentesis. However, now thoracentesis is not routinely used in all patients. VATS is performed under general anesthesia with the patient in a supine position and affected side of the chest elevated at 45 degrees to provide adequate exposure and prevent secretion overflow. A single endotracheal tube is used. The first trocar is placed using an open technique in the 5th or 6th intercostal space, midaxillary line. Continuous flow of carbon dioxide is used for lung deflation. There is a risk of displacement of the mediastinum, which can lead to impaired oxygenation, decreased venous return to the heart and carbon dioxide retention. This is especially concerning in small children, such as the patient in this case, due to the mediastinum being displaced more easily. The benefits of VATS, however, outweighed the risk in this case since the patient already experienced mediastinal shift from the progressing infection. VATS, therefore, became critical for resolution of the ravaging infection. Several recent studies suggest that VATS and fibrinolytics decrease the need for reintervention and length of hospitalization, as well as improve health outcomes in comparison with tube thoracostomy alone [17, 18].
Several pediatric studies of empyema management demonstrate that the use of VATS results in earlier, more complete resolution of the infection and decreased hospitalization in comparison with chest tube drainage and medical management. When VATS was compared with fibrinolytic agents as initial therapy for empyema in pediatric studies, there was no significant difference in length of hospital stay, failure rate, days of oxygen requirements, analgesic requirement, and radiologic outcomes [18, 19]. Our patient's presentation provided a clear need for procedural intervention that ultimately cleared enough of her rampant infection, whether bacterial or viral, to allow for complete, eventual resolution of the infection. While she has experienced sequalae that will continue to be monitored, the benefits of these procedures certainly outweighed the cost in her case.
A total of 13 different systemic antibacterials were used as empiric treatment in patients with viral pneumonia without bacterial coinfection for a total of 466 DOT. Vancomycin (50.7 %), cefepime (40.3 %), azithromycin (40.3 %), meropenem (23.9 %), and linezolid (20.9 %) were the most frequently used empiric antibacterials in patients with viral pneumonia without bacterial coinfection (Fig. 3). The most common regimens used in viral pneumonia without bacterial coinfection were vancomycin plus cefepime (28.4 %) and vancomycin plus meropenem (13.4 %). A total of 44 (65.7 %) patients with viral pneumonia without bacterial coinfection received empiric MRSA coverage with vancomycin or linezolid. Empiric antibacterial therapy was continued for a median of 4.1 days (interquartile range, 2.5–6.1 days) in viral pneumonia without bacterial coinfection, with most (69 %) being days on intravenous antibacterials.
Total antibacterial exposure differed between the long-course and short-course groups at 2116 and 484 DOT/1000PD, respectively (Fig. 3). Patients with mixed viral and bacterial infections received a total of 780 DOT/1000PD of systemic antibacterials. Median total antibacterial DOT/1000PD was also significantly higher in the long-course group compared with the short-course group (12.2 vs. 6.4; P <0.001) and the mixed-infection group (12.2 vs. 6.3; P <0.001). The most common antibacterials used were similar between groups: cefepime (long-course group: 73.1 %; short-course group: 50 %; mixed-infection group: 58.2 %), meropenem (long-course group: 37.3 %; short-course group: 32.1 %; mixed-infection group: 43.0 %), and linezolid (long-course group; 31.3 %; short-course group: 25 %; mixed-infection group: 41.7 %). Vancomycin was more commonly used in the long-course group compared with the mixed-infection group (80.6 vs. 59.5 %; P = 0.007) but not compared with the short-course group (80.6 vs. 57.1 %; P = 0.081). Azithromycin use was less prevalent in the mixed-infection group compared with the long-course group (48.1 % vs. 67.2 % of patients; P = 0.029) and the short-course group (48.1 vs. 71.4 %; P = 0.047).
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.
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).
In the present systematic review and meta-analysis, the use of corticosteroids increased mortality, ICU LOS, and the rate of secondary infection in patients with influenza pneumonia but did not influence MV days.
Our analysis demonstrates that corticosteroids not only increase mortality but also prolong ICU LOS. There are several potential mechanisms that could underlie the higher mortality and ICU LOS observed in patients who received corticosteroids. First, corticosteroids reduce systemic inflammation. Once attacked by the virus, the immune system is activated. Corticosteroids inhibit immune reactions by suppressing inflammatory reactions, preventing the migration of inflammatory cells from the circulation to issues by suppressing the synthesis of chemokines and cytokines, and inhibiting immune responses mediated by T cells and B cells [25, 26]. Thus, the alterations in immune reactions caused by corticosteroids might lead to prolonged virus viremia and delay viral clearance, ultimately increasing the risk of mortality [6, 27]. One of our included studies showed that patients who received corticosteroids had lower procalcitonin levels (0.5 vs 0.7 ng/mL, P = 0.02), while another showed that the patients who died had a higher rate of immunosuppression (34.7% vs. 15.1%, P = 0.02). Second, our analysis found that patients who received corticosteroids were more likely to develop secondary bacterial pneumonia due to immunosuppression. In addition, longer ICU LOS has also been shown to contribute to secondary infection. Third, due to immune-suppressing effects of corticosteroids, the risk of developing critical illness is increased in corticosteroid-treated patients. One study found that the rate of shock was 8% in the corticosteroid group and 4.4% in the control group. In addition, the invasive MV rate was also increased by corticosteroids, at 38.4% in the corticosteroid group and 4.5% in the control group. Fourth, other corticosteroid-related adverse outcomes, such as cardiovascular events, including fluid retention, premature atherosclerotic disease, and arrhythmias, also increased mortality in patients with influenza pneumonia [30–32]. In the included studies, patients who used more vasopressors had higher mortality. Thus, the above mechanisms may contribute to why patients with influenza pneumonia had higher mortality.
We also performed a subgroup analysis according to viral types. In all types of influenza virus, mortality was higher in those treated with corticosteroids than in controls, although symptoms were more rapidly progressive patients and the risk of ARDS higher in patients infected with H7N9 [1, 2]. Moreover, we included more large sample studies than were included in previous meta-analyses related to influenza. In addition, we focused only on patients with influenza pneumonia and not on those infected with influenza alone or those with influenza who were admitted to the ICU. Influenza pneumonia has been shown to be related to life-threatening respiratory failure and mortality; however, not all patients infected with influenza develop influenza pneumonia. In the present study, we tried to determine whether patients who develop influenza pneumonia benefit from corticosteroids. Nevertheless, we may have omitted patients with influenza pneumonia who were included in trials that studied all influenza patients, and this may have influenced the final results of our analysis.
Studies exploring the effects of corticosteroids on patients with community-based pneumonia have produced positive results. The main reason for these findings is that those infected by bacteria benefit from corticosteroids when given appropriate antibiotic therapy. The early use of antiviral therapy could also reduce mortality. Seven studies reported the use of antiviral therapy. On the one hand, we did not explore the exact role of antiviral therapy in the effects of corticosteroids due to a lack of raw data. On the other hand, we also only included patients who developed influenza pneumonia, which resulted in the included cases being more severe than those included in studies in which patients using antiviral therapy were included.
Moreover, patients who received corticosteroids were more likely to have a superinfection, such as secondary bacterial pneumonia or invasive fungal infection, and exacerbation of underlying conditions, and they also had more prolonged ICU LOS than was found in the no-corticosteroid group. In addition, one study showed that the use of corticosteroids delayed the initiation of neuraminidase inhibitors, with ICU LOS longer in patients who did not receive neuraminidase inhibitors within 5 days of illness.
In terms of MV days, corticosteroids did not seem to make a difference. However, only three studies in our analysis reported data on MV days, and the insignificant results might therefore be due to the fact that we had such a small sample size. In other words, a type II error might have occurred because of the limited number of patients.
Other than the aforementioned reasons, the effects of corticosteroids could also be influenced by the following three factors. First, the condition of the respiratory system could be responsible. Corticosteroids can provide benefits to patients with an oxygenation index (OI; partial arterial pressure of oxygen/fraction of inspired oxygen) < 300, but it may also increase the 60-day mortality rate in those with OI > 300. Second, the time of corticosteroid initiation could be a contributing factor. Compared with no treatment, administration within the first 3 days was more strongly associated with an increased risk of death [13, 36]. Moreover, corticosteroids are beneficial if used early after ARDS onset but otherwise increase mortality. In reality, however, some patients received corticosteroids after ARDS onset, which offset the negative effect of corticosteroids on mortality. Third, the dose of corticosteroids may affect results. High doses of corticosteroids have been associated with greater mortality and a longer duration of viral shedding. In Li’s study, mortality was twice as high in patients who received a high dose of corticosteroids than in those who received a low-moderate dose. The initial dose of corticosteroids varied among our included studies, and some of them did not report related information. Additionally, due to the study design, not all patients in one study received a unified dose of corticosteroids. Moreover, studies have shown that corticosteroids are usually initiated when shock is non-responsive to fluids and vasopressors. Thus, patients who receive corticosteroids tend to have more severe disease, as evidenced by their higher APACHE II scores. It is therefore unclear whether their increased risk of mortality is directly associated with corticosteroid use or due to the severity of disease. None of the studies included in our analysis was a randomized controlled study (RCT). Because the influencing factors could not be controlled, our analysis was highly heterogeneous. This might explain why corticosteroids did not make a difference in some studies.
Despite these findings, the limitations of our study should be addressed. First, the applicability of our study results is limited because none of the studies included in our analysis was an RCT. Second, only two studies reported the dose of corticosteroids and the duration of it use. Third, the baseline characteristics of the patients can influence outcomes and varied among the studies included in our analysis. For example, younger age and fewer underlying diseases might be associated with fewer secondary infections. Finally, the effect of corticosteroids on patients with influenza pneumonia remains controversial. Previous studies that showed a negative effect for corticosteroids may have influenced how the clinicians used corticosteroids in our included studies. Finally, there may have been selection bias because none of the studies included was an RCT.