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Prednisone treatment for flu.The Best Flu Treatment For You
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A principal resource for the optimal clinical therapy of influenza A H1N1 patients and directions for future research are warranted. We therefore conducted the present study to determine whether corticosteroids can treat severe H1N1 infection.
To clarify the association of corticosteroids with H1N1 mortality taking into account clinical status and study design, we examined the associations in larger, prospective cohort studies in global settings, using existing literature, and assessed the effect of corticosteroids treatment on mortality through meta-analysis.
We conducted a comprehensive literature search both for English-language and Chinese-language articles examining the effect of corticosteroid treatment in influenza A H1N1 published up until October We contacted article authors for further information or clarification when necessary. No attempt was made to include unpublished data. All searches were executed independently by two skilled researchers.
In addition, the reference lists of retrieved original articles and of relevant systematic reviews were manually checked. No ethics board approval was deemed necessary for a meta-analysis of previously published studies.
Because there was no randomized trial available, we included both cohort studies and case—control studies. We included cohort studies fulfilling the following selection criteria: enrolled patients had confirmed, probable, or suspected influenza A H1N1 ; all of the subjects were inpatient, or admitted to the ICU, or critically ill; corticosteroid treatment was compared with noncorticosteroid treatment within the cases; and data about hospital mortality were accessible.
For case—control studies, the inclusion criteria were that: enrolled patients had confirmed, or had probable or were suspected of having influenza A H1N1 ; all of the subjects were inpatient, or admitted to the ICU, or critically ill; deaths were cases and survivors were controls; and the numbers of patients who received or did not receive steroid treatment were presented in two groups.
There were no restrictions on studies with respect to age groups. Studies were excluded if they: included seasonal influenza infection cases; were in vitro tests, animal experiments, case studies, case series, and review or letter articles; and targeted special crowds, such as pregnant women and patients with HIV infections. Additionally, confirmed influenza A H1N1 cases were defined as an acute respiratory illness with laboratory confirmation by real-time PCR or viral culture.
Corticosteroid treatment was defined as: systemic corticosteroid use; and nonstandardized corticosteroid use, which was decided by the attending physician and was regardless of type, dosage, and frequency of administration.
All full articles were reviewed for the selection and exclusion of publications with predefined inclusion criteria by two researchers independently. We also contacted the corresponding author of 12 studies by email to ask for additional details. However, only three authors responded. For case—control studies, we collected information about the numbers of patients treated with steroids in each group. With regard to cohort studies, information about the number of patients who died in each group and other clinical outcomes were collected.
Disagreements were resolved by consensus. The Newcastle-Ottawa Scale scoring system was used to assess the methodology and quality of both cohort studies and case—control studies [ 29 ]. The Newcastle-Ottawa Scale assigns a maximum score of 4 for selection, 2 for comparability, and 3 for exposure case—control studies or outcome cohort studies. Hence, a score of 9 is the highest possible and reflects the best quality. Two investigators independently assessed the risk of bias of each study.
The detailed evaluation criteria are shown in Additional file 1. Inter-rater agreement was assessed using Cohen's kappa statistics and disagreements were resolved by consensus. We calculated the relative risk for death within cohort studies, while the odds ratio OR was used for case—control studies. Heterogeneity of treatment effects among studies was assessed by examining forest plots, and statistically using Cochran Q and I 2 statistics. If a significant heterogeneity was identified, subgroup analyses were carried out.
Studies were categorized by sample size, by whether the subjects from two groups are comparable in terms of age and antiviral treatment, and by whether the studies included probable and suspected A H1N1 cases. Sensitivity analysis excluded studies one by one to investigate the heterogeneity.
The sponsor of this study had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the paper for publication. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit the paper for publication.
Of the 2, references screened, 23 studies were included in the final analysis Figure 1. Fourteen studies were case—control studies [ 15 , 31 - 43 ], and nine studies were cohort studies [ 44 - 52 ]. In total, 6, subjects were analyzed, with 4, subjects in case—control studies and 1, subjects in cohort studies. Among these studies, seven studies were conducted in China [ 36 , 39 , 41 - 44 , 50 ], three in Spain [ 33 , 45 , 49 ], three in India [ 31 , 35 , 46 ], two in Korea [ 18 , 28 ], two in Argentina [ 15 , 40 ], and one study each was conducted in Mexico [ 37 ], Turkey [ 38 ], Saudi Arabia [ 48 ], France [ 51 ], and Finland [ 52 ], while the remaining study was multicenter and conducted in several countries European Society of Intensive Care Medicine [ 47 ].
The characteristics of the included studies are summarized in Table 1. Participants in all studies were inpatients. Eighteen studies only included patients in the ICU or critically ill cases [ 15 , 32 - 36 , 38 - 40 , 42 , 44 , 46 - 52 ], and three studies included children [ 35 , 36 , 40 ].
There was only one study that did not mention antiviral treatment use in patients [ 44 ]. Corticosteroid treatment varied among these studies, with most using methylprednisolone or hydrocortisone; doses varied from 80 to mg daily. However, there were still several studies which did not describe the tapering doses in detail, or the precise duration of treatment. Two Spanish studies showed that corticosteroid administrations were not standardized and were decided by the attending physician without detailed data [ 33 , 49 ].
Another six studies did not provide any detailed information about dose, duration, and treatment mode [ 34 , 40 , 42 - 44 , 52 ]. The overall quality of the included studies was moderate and the analyses are presented in Figure 2 and Figure 3. Most studies were retrospective and observational studies, and the most common bias was lack of comparability in terms of age or antiviral therapy between study groups.
In addition, some studies did not provide detailed data with regard to corticosteroid use. Most of the study data were obtained either from the registration systems or by reviewing hospital records, and the response rate was not reported.
They were therefore judged as high risk in this respect. Only a few studies demonstrated that they excluded steroid-use cases for underlining diseases, while other studies did not mention this at all.
Effect of corticosteroids on influenza A H1N1 cases from case—control studies. Diamond, overall estimate from the meta-analysis; square, point estimate of the result of each study; horizontal line that runs through the square and the width of the diamond represents the CI.
Red dot, high risk of bias; green dot, low risk of bias; A to I, see Additional file 1. Effect of corticosteroids on influenza A H1N1 cases from cohort studies. The random-effects model was therefore used and the combined OR was 4. Subgroup analysis was conducted to investigate the heterogeneity, and the results are shown in Additional file 2.
The plots show that the sample size of studies, as well as comparability in terms of age and antiviral treatment, did not significantly influence the final mortality outcome. The heterogeneity was not statistically significant, after studies were categorized according to whether they enrolled suspected or probable cases, and the pooled OR was 5. Subgroup analyses, as shown in Additional file 3 , revealed that the relative risk was higher in studies of poor quality than that of the good quality studies.
However, the difference was not statistically significant. Besides, the inclusion of probable and suspected cases did not significantly change the result, consistently showing steroid treatment was a risk factor of mortality. Similarly, another Chinese study indicated that patients in steroid treatment groups have a shorter duration of fever and a shorter duration of inflammation [ 50 ].
Also, Linko and colleagues study showed that the length of ICU and hospital stay was significantly longer in the patients treated with corticosteroids [ 52 ].
Regarding the duration of mechanical ventilation, Diaz and colleagues displayed that there was no difference between the corticosteroid and noncorticosteroid groups [ 49 ]. However, the funnel plots provided evidence of publication bias for both types of studies Additional file 4. During the influenza pandemic, the debate over whether to use corticosteroid treatment in severe influenza H1N1-infected patients resurfaced and was disputed by clinicians [ 26 ].
According to our review, corticosteroid administration is likely to increase mortality in patients with influenza A H1N1 , and the trend is consistent regardless of the quality as well as the sample size of studies. Apart from the studies included in this meta-analysis, there are many studies that refer to the steroids used and the outcomes, and most of them reported that corticosteroids have negative effects or no effect on H1N1 treatment.
For example, Balaganesakumar and colleagues found that corticosteroid treatment would cause a higher risk of poor patient outcomes [ 54 ]. Other reports showed that patients who received corticosteroids were more likely to develop secondary bacterial pneumonia [ 47 , 55 ] or were associated with an increased risk of developing critical illness, with ICU admission, or had more prolonged ICU stays [ 17 , 55 - 57 ].
The possible explanation for the negative effectiveness of corticosteroids might be that corticosteroids could inhibit immune reactions. However, immune systems should be activated in order to eliminate the virus [ 58 ]. Altered immune reactions thus might lead to prolonged virus viremia [ 59 ] and delay viral clearance [ 60 ], and ultimately increase the risk of mortality. Indeed, there are several studies that reveal the positive role of corticosteroids, but most of them used animal models [ 61 ] or case series that lacked a control group [ 22 , 24 ].
Therefore, it might be difficult to draw conclusions that corticosteroids have any advantages over nonuse corticosteroids. Besides, although previous studies suggested that the clinical outcome in patients hospitalized with CAP was improved by systemic corticosteroids [ 13 ], researchers pointed out that these studies included predominantly CAP cases with bacterial infection and were given appropriate antibiotic therapy; thus, the encouraging results cannot be popularized to all CAP, especially those with viral infection [ 8 ].
Nevertheless, our study has some limitations. Firstly, heterogeneity cannot be ignored in our research. Since it is impossible to conduct a clinical trial on critically ill patients, only observational studies were retrieved and enrolled in our meta-analysis.
While observational studies are potentially susceptible to bias and induce between-study heterogeneity due to clinical diversity, we cannot draw a robust conclusion.
Second, as noticed by clinicians, critical patients were more likely to be given steroids than patients with mild cases [ 52 , 62 ]; the severity of illness should therefore be taken into account. Among the 23 included research papers, 17 studies conducted further multivariable analysis to adjust for potential confounding factors and to determine whether corticosteroid treatment is a predictor of mortality.
Among these, 14 studies showed that corticosteroid treatment was not an independent risk factor for mortality, although there was a trend towards greater mortality, while the remaining three studies suggested that corticosteroid treatment could increase the mortality risk independently.
Through the reality of the abovementioned factors, we cannot draw a solid conclusion about the effectiveness of corticosteroids in treating severe influenza A H1N1 cases. Besides, it is difficult to evaluate fairly the effect according to the dose, time given, and baseline of steroid use, because steroid usage was varied by the attending physician and very few studies gave detailed information about it.
Hence, further clinical studies — especially those with a comparative and rigorous design regarding the timing, the formulation of corticosteroids, the dosage, the duration, and the length of tapering — as well as randomized studies may help to clarify this issue. Our findings suggest that corticosteroids have no beneficial effects in treating patients with influenza A H1N1.
A stronger study design and data replication are necessary moving forward. Cao, B. Delaney, J. The influence of corticosteroid treatment on the outcome of influenza A H1N1pdm09 -related critical illness. Wirz, S. Pathogen- and antibiotic-specific effects of prednisone in community-acquired pneumonia.
Brun-Buisson, C. Li, H. Effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza A H1N1 pdm09 viral pneumonia.
Xi, X. Hospitalized adult patients with influenza A H1N1 in Beijing, China: risk factors for hospital mortality. Huang, S. Effects of corticosteroid and neuraminidase inhibitors on survival in patients with respiratory distress induced by influenza virus. Chawla, R. Predictors of mortality and length of stay in hospitalized cases of influenza A H1N1 : Experiences of a tertiary care center.
Linko, R. Viasus, D. Effect of immunomodulatory therapies in patients with pandemic influenza A H1N1 complicated by pneumonia. Chien, Y. Predictors and outcomes of respiratory failure among hospitalized pneumonia patients with H1N1 influenza in Taiwan.
Stang, A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in metaanalyses. Carrillo-Esper, R. Experience in the management of the severe form of human influenza A H1N1 pneumonia in an intensive care unit. Cirugia y cirujanos 79 , — PubMed Google Scholar. Rios, F. Lung function and organ dysfunctions in patients requiring mechanical ventilation during the influenza A H1N1 pandemic.
Article Google Scholar. Sertogullarindan, B. Clinical and prognostic features of patients with pandemic influenza a H1N1 virus in the intensive care unit. African Health Sciences 11 , — Lee, N. Neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients.
Kinikar, A. Predictors of mortality in hospitalized children with pandemic H1N1 influenza in Pune, India. Kil, H. Early corticosteroid treatment for severe pneumonia caused by H1N1 influenza virus.
Kudo, K. Systemic corticosteroids and early administration of antiviral agents for pneumonia with acute wheezing due to influenza A H1N1 pdm09 in Japan. Balaganesakumar, S.
Dellinger, R. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: Brundage, J. Deaths from bacterial pneumonia during influenza pandemic. Morens, D. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness.
Viral loads and duration of viral shedding in adult patients hospitalized with influenza. To, K. Delayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 influenza virus infection. Ernst, P. Differences between asthmatics and nonasthmatics hospitalised with influenza A infection.
Rhodes, A. Bekkat-Berkani, R. Seasonal influenza vaccination in patients with COPD: a systematic literature review. Quispe-Laime, A. H1N1 influenza A virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment.
Athauda, D. Ni, Y. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Lansbury, L. Corticosteroids as adjunctive therapy in the treatment of influenza. Rodrigo, C. Download references. You can also search for this author in PubMed Google Scholar. Shigui Yang designed the study. Yuqing Zhou and Shigui Yang interpreted the results.
Yuqing Zhou wrote the manuscript. Yuqing Zhou and Shigui Yang revised the manuscript from preliminary draft to submission. Shigui Yang supervised the study. Correspondence to Shigui Yang. Reprints and Permissions. Zhou, Y. Use of corticosteroids in influenza-associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis.
Sci Rep 10 , Download citation. Received : 27 August Accepted : 03 February Published : 20 February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. By submitting a comment you agree to abide by our Terms and Community Guidelines.
If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Download PDF. Subjects Drug therapy Influenza virus. Abstract Influenza-related severe pneumonia and acute respiratory distress syndrome ARDS are severe threats to human health.
Introduction Influenza is a viral infection that attacks the respiratory system. Data extraction and quality assessment Outcome data were independently extracted from the included studies by two investigators using a previously piloted standardized pro forma.
Sensitivity analysis We performed sensitivity analysis to assess the effect of the study design on clinical outcomes using stratification if the number of studies was sufficient. In homeopathy, a presumed active ingredient—in Oscillococcinum, it's an extract of wild duck heart and liver—is diluted to the point where it's virtually undetectable.
According to Lipman, there's no good evidence that homeopathy works. Consumer Reports reached out to Boiron, the manufacturers of Oscillococcinum. In an emailed statement, a Boiron representative wrote, "Oscillococcinum has remarkable customer satisfaction and a money-back guarantee. The statement also said: "Oscillococcinum has been shown in two placebo-controlled, double-blind, randomized clinical trials to help reduce the severity and shorten the duration of flu-like symptoms.
What should you do if you've got the flu? Unless you're a candidate for an antiviral, our experts recommend strategies such as rest, getting plenty of fluids, and the use of OTC pain relievers as directed by your doctor. You can also follow the Consumer Reports' day-by-day guide to treating colds and flu. While most studies on masks have been done in healthcare settings, some suggest they may help stave off flu in other situations, too. It may also help prevent you from passing the virus from your hands to your mouth or nose.
And wear one if you're sick and are going to be around other people, or are caring for someone with the flu. Last, consider a mask if you're going to a doctor's office, or if you're traveling on an airplane, especially if people around you seem sick.
Two types of masks are currently available: surgical masks available at drugstores and online , designed to block large particles that may carry viruses, and N respirators available at some hardware, medical supply, and office supply stores and online , which block even smaller particles. Both appear to work equally well, according to a study in JAMA. Just make sure you get a tight fit around your mouth and nose.
For more advice on masks and the flu, see what the CDC says. But these only work for bacterial infections—not viral infections like the flu. And using the medications unnecessarily can contribute to an increase in antibiotic-resistant bacteria and bacterial infections that are hard or impossible to cure, Lipman says.
The flu can sometimes, however, lead to complications that may be appropriate to treat with antibiotics, such as bacterial pneumonia. Secondary infections such as strep throat may be treated with antibiotics, too, says pharmacist Heather Free. Some doctors may also prescribe steroids such as prednisone to stem symptoms like the cough that can occur due to inflammation from the flu virus.
We respect your privacy. All email addresses you provide will be used just for sending this story. Certain of these "alternative" flu therapies, such as dietary supplementsare even being recommended by some pharmacists, according to news accounts.
More people are also donning surgical or respiratory masks to keep flu germs at bay. And some are getting prescriptions for steroids and antibiotics if they do come down with the virus. Do any of these strategies actually work?
And what should you do if you can't find an antiviral like Tamiflu, or a place to get a flu shot? Newspapers and TV stations around the U. These drugs can reduce flu symptoms somewhat and may shorten the course of the flu.
According to the Centers for Disease Control and Prevention CDCthere have been spot shortages of the vaccine and the antivirals, particularly of generic oseltamivir in capsule and powder form which is mixed with water for those who have trouble swallowing capsules. Confirm by phone before you go and be aware, says the CDC, that you may not have a choice about which flu shot you get. If you have just come down with the flu and your doctor thinks you're a candidate for an antiviral —most otherwise healthy people generally are not—it may take a bit of detective work to find it, says Michael Hochman, M.
At his center, the nurses keep up with which pharmacies have antivirals in stock, so ask whether your doctor's office has similar information. Or check pharmacy websites—some are noting availability of antivirals—or call local drugstores.
Good to know: If you need powder oseltamivir and it's out of stock, pharmacists now have permission from the CDC to compound it from capsules. If cost is a concern, know that many health insurers are currently covering Tamiflu as a generic or at the lowest cost "tier" for brand-name drugs. Lipman, M. In the case of one vitamin—vitamin D—some research does suggest that supplements may modestly reduce the risk of upper respiratory infection such as a cold or flu.
But those results were mainly seen in people who were very deficient in the vitamin. And, notes Heather Free, Pharm D. Homeopathic productswhich are classified by the FDA as medications and may sit on drugstore shelves next to over-the-counter drugs, are a different matter. In homeopathy, a presumed active ingredient—in Oscillococcinum, it's an extract of wild duck heart and liver—is diluted to the point where it's virtually undetectable.
According to Lipman, there's no good evidence that homeopathy works. Consumer Reports reached out to Boiron, the manufacturers of Oscillococcinum. In an emailed statement, a Boiron representative wrote, "Oscillococcinum has remarkable customer satisfaction and a money-back guarantee.
The statement also said: "Oscillococcinum has been shown in two placebo-controlled, double-blind, randomized clinical trials to help reduce the severity and shorten the duration of flu-like symptoms.
What should you do if you've got the flu? Unless you're a candidate for an antiviral, our experts recommend strategies such as rest, getting plenty of fluids, and the use of OTC pain relievers as directed by your doctor. You can also follow the Consumer Reports' day-by-day guide to treating colds and flu. While most studies on masks have been done in healthcare settings, some suggest they may help stave off flu in other situations, too.
It may also help prevent you from passing the virus from your hands to your mouth or nose. And wear one if you're sick and are going to be around other people, or are caring for someone with the flu. Last, consider a mask if you're going to a doctor's office, or if you're traveling on an airplane, especially if people around you seem sick.
Two types of masks are currently available: surgical masks available at drugstores and onlinedesigned to block large particles that may carry viruses, and N respirators available at some hardware, medical supply, and office supply stores and onlinewhich block even smaller particles. Both appear to work equally well, according to a study in JAMA. Just make sure you get a tight fit around your mouth and nose. For more advice on masks and the flu, see what the CDC says. But these only work for bacterial infections—not viral infections like the flu.
And using the medications unnecessarily can contribute to an increase in antibiotic-resistant bacteria and bacterial infections that are hard or impossible to cure, Lipman says. The flu can sometimes, however, lead to complications that may be appropriate to treat with antibiotics, such as bacterial pneumonia. Secondary infections such as strep throat may be treated with antibiotics, too, says pharmacist Heather Free.
Some doctors may also prescribe steroids such as prednisone to stem symptoms like the cough that can occur due to inflammation from the flu virus. But this is potentially dangerous, because steroids suppress your immune system—making it harder to fight infection, says William Schaffner, M. Generally, steroids should be considered for the flu only for people who are admitted to the hospital with severe wheezing due to an underlying problem such as chronic obstructive pulmonary disease or asthma, Lipman adds.
So unless you have a bacterial infection or lung problems, avoid antibiotics and steroids for the flu. Instead, follow these treatment steps if you do get sick. Hallie Levine is an award-winning magazine and freelance writer who contributes to Consumer Reports on health and fitness topics. She's a mom to three kids and a fat but feisty black Labrador r etriever named Ivry. In her nonexistent spare time, she likes to read, swim, and run marathons. Do you need Tamiflu? Do antibiotics, steroids, and supplements work?
What you must know now. By Hallie Levine. February 14, Sharing is Nice Yes, send me a copy of this email. Send We respect your privacy. Oops, we messed up. Try again later. When you shop through retailer links on our site, we may earn affiliate commissions. Learn more. More on the Flu.
When to Worry About a Fever. More From Consumer Reports. Hallie Levine Hallie Levine is an award-winning magazine and freelance writer who contributes to Consumer Reports on health and fitness topics. Show comments commenting powered by Facebook.
We reviewed the evidence regarding the effect of additional ('adjunctive') steroid treatment in individuals with influenza infection. Administration of corticosteroids during critical illness, including severe influenza, may attenuate this state of adrenal insufficiency and. The results of our review show that corticosteroid treatment for patients with influenza virus infection does not result in better outcomes, and may be. In patients with influenza, corticosteroids have shown no benefit, as published by multiple observational studies and with the increased risk of complications. Recently, some studies have shown that corticosteroids may not be beneficial for patients with severe influenza and may even increase mortality. No attempt was made to include unpublished data. Conclusion Current data do not support the routine use of corticosteroids in patients with influenza pneumonia or ARDS. Several studies showed that prolonged viral shedding and delayed viral clearance were noted in corticosteroid-treated patients 1034whereas slower clearance of virus loads was associated with higher mortality in patients with ARDS due to H1N1pdm09 virus infectionCritical Care volume 19 , Article number: 46 Cite this article. Metrics details. Corticosteroids are used empirically in influenza A H1N1 treatment despite lack of clear evidence for effective treatment. This study aims to assess the efficacy of corticosteroids treatment for H1N1 infection.
Systematic review and meta-analysis were used to estimate the efficacy of corticosteroids for the prevention of mortality in H1N1 infection. We included both cohort studies and case-control studies reported in English or Chinese that compared treatment effects between corticosteroids and non-corticosteroids therapy in inpatients with H1N1 virus infection.
Cohort studies employed mortality as outcome, and case-control studies employed deaths as cases and survivors as controls; both were assessed in this meta-analysis.
In total twenty-three eligible studies were included. The results from both subgroup analyses and sensitive analyses were consistent with each other, showing that steroid treatment is associated with mortality. However, considering the fact that corticosteroids were tend to be used in sickest case-patients and heterogeneity was observed between studies, we cannot make a solid conclusion. Available evidence did not support the use of corticosteroids as standard care for patients with severe influenza.
We conclude that further research is required. Novel influenza A H1N1 spread around the world in spring Although influenza A H1N1 infection has a mild clinical course, the pandemic virus is capable of leading to severe illness, requiring hospitalization. As an example, the hospital admission rate for children with H1N1 influenza was twofold the rate for seasonal influenza [ 1 ].
The disease caused , deaths globally [ 6 , 7 ]. Accordingly, there is an increasing need for the development of an effective therapy and treatment to improve upon the prognosis of severe cases. In severe influenza infectious cases, cytokine dysregulation was observed in patients [ 8 ] and corticosteroids had been proven to be able to reduce systemic inflammation by inhibition of proliferation and cytokine production [ 8 - 11 ]. Previous meta-analyses of patients with acute long injury and acute respiratory distress syndrome indicated that prolonged glucocorticoid treatment is safe and is associated with significant reductions in markers of systemic inflammation, multiple organ dysfunction score, duration of mechanical ventilation, and ICU length of stay [ 11 , 12 ].
Although corticosteroids are widely used, the effect of corticosteroids on pandemic A H1N1 influenza patients has not been studied adequately and, thus, is still controversial. For example, in several studies a remarkable effect was observed of early treatment with oseltamivir and steroids for patients with severe pneumonia in preventing disease progression [ 19 - 21 ]. Additionally, a number of clinical case series and case reports have shown that patients with severe respiratory complications, pneumonia, improved after the use of corticosteroids [ 22 - 24 ].
However, the USA Centers for Disease Control and Prevention does not recommend the use of corticosteroids as a primary medicine for H1N1 infection, with the exception that a reasonable dose is indicated for a specific reason; for example, pulmonary obstruction or septic shock [ 25 ].
Moreover, World Health Organization guidelines for Pharmacological Management of Pandemic Influenza A H1N1 and other Influenza Viruses recommend that systemic corticosteroids should not be administrated to patients who have severe or progressive clinical illness unless in some exceptional circumstances [ 26 , 27 ].
Severe influenza treatment guidelines for Korea also indicate that systemic corticosteroid administration should not be performed for the treatment of severe influenza patients unless the therapeutic effect has already been proven [ 28 ].
None of the guidelines above recommend systematic corticosteroid use regularly with H1N1 infection. However, lack of clinical evidence makes these recommendations or guidelines unconvincing. Until now, many studies involving the treatment of severe H1N1 cases have been published, but the results are inconsistent, which could be due to insufficient sample sizes, complicated clinical status, or study design.
To our knowledge, there has been no systematic literature review evaluating the benefit of corticosteroids to severe H1N1 infection. A principal resource for the optimal clinical therapy of influenza A H1N1 patients and directions for future research are warranted.
We therefore conducted the present study to determine whether corticosteroids can treat severe H1N1 infection. To clarify the association of corticosteroids with H1N1 mortality taking into account clinical status and study design, we examined the associations in larger, prospective cohort studies in global settings, using existing literature, and assessed the effect of corticosteroids treatment on mortality through meta-analysis.
We conducted a comprehensive literature search both for English-language and Chinese-language articles examining the effect of corticosteroid treatment in influenza A H1N1 published up until October We contacted article authors for further information or clarification when necessary. No attempt was made to include unpublished data. All searches were executed independently by two skilled researchers.
In addition, the reference lists of retrieved original articles and of relevant systematic reviews were manually checked. No ethics board approval was deemed necessary for a meta-analysis of previously published studies. Because there was no randomized trial available, we included both cohort studies and case—control studies. We included cohort studies fulfilling the following selection criteria: enrolled patients had confirmed, probable, or suspected influenza A H1N1 ; all of the subjects were inpatient, or admitted to the ICU, or critically ill; corticosteroid treatment was compared with noncorticosteroid treatment within the cases; and data about hospital mortality were accessible.
For case—control studies, the inclusion criteria were that: enrolled patients had confirmed, or had probable or were suspected of having influenza A H1N1 ; all of the subjects were inpatient, or admitted to the ICU, or critically ill; deaths were cases and survivors were controls; and the numbers of patients who received or did not receive steroid treatment were presented in two groups. There were no restrictions on studies with respect to age groups. Studies were excluded if they: included seasonal influenza infection cases; were in vitro tests, animal experiments, case studies, case series, and review or letter articles; and targeted special crowds, such as pregnant women and patients with HIV infections.
Additionally, confirmed influenza A H1N1 cases were defined as an acute respiratory illness with laboratory confirmation by real-time PCR or viral culture. Corticosteroid treatment was defined as: systemic corticosteroid use; and nonstandardized corticosteroid use, which was decided by the attending physician and was regardless of type, dosage, and frequency of administration.
All full articles were reviewed for the selection and exclusion of publications with predefined inclusion criteria by two researchers independently. We also contacted the corresponding author of 12 studies by email to ask for additional details. However, only three authors responded.
For case—control studies, we collected information about the numbers of patients treated with steroids in each group. With regard to cohort studies, information about the number of patients who died in each group and other clinical outcomes were collected. Disagreements were resolved by consensus. The Newcastle-Ottawa Scale scoring system was used to assess the methodology and quality of both cohort studies and case—control studies [ 29 ]. The Newcastle-Ottawa Scale assigns a maximum score of 4 for selection, 2 for comparability, and 3 for exposure case—control studies or outcome cohort studies.
Hence, a score of 9 is the highest possible and reflects the best quality. Two investigators independently assessed the risk of bias of each study. The detailed evaluation criteria are shown in Additional file 1. Inter-rater agreement was assessed using Cohen's kappa statistics and disagreements were resolved by consensus.
We calculated the relative risk for death within cohort studies, while the odds ratio OR was used for case—control studies. Heterogeneity of treatment effects among studies was assessed by examining forest plots, and statistically using Cochran Q and I 2 statistics. If a significant heterogeneity was identified, subgroup analyses were carried out.
Studies were categorized by sample size, by whether the subjects from two groups are comparable in terms of age and antiviral treatment, and by whether the studies included probable and suspected A H1N1 cases. Sensitivity analysis excluded studies one by one to investigate the heterogeneity. The sponsor of this study had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the paper for publication.
The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit the paper for publication. Of the 2, references screened, 23 studies were included in the final analysis Figure 1. Fourteen studies were case—control studies [ 15 , 31 - 43 ], and nine studies were cohort studies [ 44 - 52 ].
In total, 6, subjects were analyzed, with 4, subjects in case—control studies and 1, subjects in cohort studies. Among these studies, seven studies were conducted in China [ 36 , 39 , 41 - 44 , 50 ], three in Spain [ 33 , 45 , 49 ], three in India [ 31 , 35 , 46 ], two in Korea [ 18 , 28 ], two in Argentina [ 15 , 40 ], and one study each was conducted in Mexico [ 37 ], Turkey [ 38 ], Saudi Arabia [ 48 ], France [ 51 ], and Finland [ 52 ], while the remaining study was multicenter and conducted in several countries European Society of Intensive Care Medicine [ 47 ].
The characteristics of the included studies are summarized in Table 1. Participants in all studies were inpatients. Eighteen studies only included patients in the ICU or critically ill cases [ 15 , 32 - 36 , 38 - 40 , 42 , 44 , 46 - 52 ], and three studies included children [ 35 , 36 , 40 ].
There was only one study that did not mention antiviral treatment use in patients [ 44 ]. Corticosteroid treatment varied among these studies, with most using methylprednisolone or hydrocortisone; doses varied from 80 to mg daily.
However, there were still several studies which did not describe the tapering doses in detail, or the precise duration of treatment.
Two Spanish studies showed that corticosteroid administrations were not standardized and were decided by the attending physician without detailed data [ 33 , 49 ].
Another six studies did not provide any detailed information about dose, duration, and treatment mode [ 34 , 40 , 42 - 44 , 52 ]. The overall quality of the included studies was moderate and the analyses are presented in Figure 2 and Figure 3. Most studies were retrospective and observational studies, and the most common bias was lack of comparability in terms of age or antiviral therapy between study groups.
In addition, some studies did not provide detailed data with regard to corticosteroid use. Most of the study data were obtained either from the registration systems or by reviewing hospital records, and the response rate was not reported.
They were therefore judged as high risk in this respect. Only a few studies demonstrated that they excluded steroid-use cases for underlining diseases, while other studies did not mention this at all. Effect of corticosteroids on influenza A H1N1 cases from case—control studies.
Diamond, overall estimate from the meta-analysis; square, point estimate of the result of each study; horizontal line that runs through the square and the width of the diamond represents the CI. Red dot, high risk of bias; green dot, low risk of bias; A to I, see Additional file 1. Effect of corticosteroids on influenza A H1N1 cases from cohort studies.
The random-effects model was therefore used and the combined OR was 4. Subgroup analysis was conducted to investigate the heterogeneity, and the results are shown in Additional file 2.
The plots show that the sample size of studies, as well as comparability in terms of age and antiviral treatment, did not significantly influence the final mortality outcome. The heterogeneity was not statistically significant, after studies were categorized according to whether they enrolled suspected or probable cases, and the pooled OR was 5.
Subgroup analyses, as shown in Additional file 3 , revealed that the relative risk was higher in studies of poor quality than that of the good quality studies. However, the difference was not statistically significant. Besides, the inclusion of probable and suspected cases did not significantly change the result, consistently showing steroid treatment was a risk factor of mortality.
Similarly, another Chinese study indicated that patients in steroid treatment groups have a shorter duration of fever and a shorter duration of inflammation [ 50 ]. Also, Linko and colleagues study showed that the length of ICU and hospital stay was significantly longer in the patients treated with corticosteroids [ 52 ].
Regarding the duration of mechanical ventilation, Diaz and colleagues displayed that there was no difference between the corticosteroid and noncorticosteroid groups [ 49 ]. However, the funnel plots provided evidence of publication bias for both types of studies Additional file 4.
During the influenza pandemic, the debate over whether to use corticosteroid treatment in severe influenza H1N1-infected patients resurfaced and was disputed by clinicians [ 26 ]. According to our review, corticosteroid administration is likely to increase mortality in patients with influenza A H1N1 , and the trend is consistent regardless of the quality as well as the sample size of studies.
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