Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia

doi:10.1016/j.jinf.2011.01.014

Journal of Infection

Volume 62, Issue 3, March 2011, Pages 193-199

https://doi.org/10.1016/j.jinf.2011.01.014 Get rights and content

Summary

Objective

To determine the effect of immunomodulatory therapies on the development of severe disease in hospitalized adults with laboratory-confirmed pandemic influenza A (H1N1) 2009 complicated by pneumonia.

Methods

Observational, prospective cohort study at thirteen tertiary hospitals in Spain. The use of corticosteroids, macrolides and statins was recorded. The outcome of interest was severe disease, defined as the composite of intensive care unit admission or death after the first day of hospitalization.

Results

Of the 197 patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia, 68 (34.5%) received some anti-inflammatory therapy since hospital admission (corticosteroids in 37, macrolides in 31 and statins in 12). Severe disease occurred in 29 (14.7%) patients. After adjustment for confounding factors, immunomodulatory therapies as a group were not associated with a lower risk for developing severe disease (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.22–1.86). In a further a priori analysis, corticosteroids, macrolides and statins were included in a multivariate model. None of these therapies was found to be associated with a lower risk for developing severe disease.

Conclusions

Immunomodulatory therapies use since hospital admission did not prevent the development of severe disease in adults with pandemic influenza A (H1N1) 2009 complicated by pneumonia.

Introduction

There is evidence that some of the most severe effects of the 1918 H1N1 or avian H5N1 influenza virus infection are related to the uncontrolled response of the immune system.¹ In this regard, Bermejo-Martin et al.² and To et al.³ found that increased systemic levels of pro-inflammatory cytokines constituted a hallmark in severe cases of pandemic (H1N1) 2009. It has been suggested, therefore, that immunomodulatory adjunctive therapies, in addition to the antiviral drugs, could be useful in reducing morbidity and mortality during influenza pandemics.4, 5, 6 Corticosteroids, macrolides and hydroxymethylglutaryl-CoA reductase inhibitors (statins) possess anti-inflammatory properties that are thought to have beneficial effects during influenza infection.4, 5, 7 However, no prospective study has evaluated whether these therapies are able to prevent complications during influenza A (H1N1) 2009 virus infection.

The aim of this study was to determine the effect of anti-inflammatory therapies (corticosteroids, macrolides and statins) on the development of severe disease in hospitalized patients with pandemic influenza A (H1N1) 2009 virus infection complicated by pneumonia.

Section snippets

Study design and patients

This observational prospective cohort study was carried out at thirteen tertiary hospitals in Spain. All nonimmunosuppressed adults admitted to hospital for at least 24 h with influenza A (H1N1) 2009 virus infection complicated by pneumonia from 12 June to 10 November, 2009 were included. All patients had an influenza-like illness with laboratory-confirmed pandemic influenza A (H1N1) 2009 virus infection by real-time reverse-transcription polymerase chain reaction (RT-PCR) or viral culture.

Results

During the study period a total of 234 patients required hospitalization due to pandemic influenza A (H1N1) 2009 complicated by pneumonia. Thirty-seven patients were excluded from the analyses because 29 were immunosuppressed, 21 required ICU at hospital admission and 5 patients did not have data on the use of any of the anti-inflammatory therapies. Among the 197 patients analyzed, 146 (74.1%) had primary viral pneumonia and 28 (14.2%) had concomitant/secondary bacterial pneumonia. Bacterial

Discussion

To our knowledge, no previous study has analyzed the effect of anti-inflammatory therapies in hospitalized patients with pandemic influenza A (H1N1) 2009 virus infection. In the present observational analysis of a prospective cohort of nonimmunosuppressed adult patients with pandemic (H1N1) 2009 complicated by pneumonia, patients on anti-inflammatory therapies (corticosteroids, macrolides and statins) since hospital admission did not have a decreased risk for developing severe disease after the

Acknowledgments

This study was supported by the Spain’s Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, Programa de Investigación sobre gripe A/H1N1 (Grant: GR09/0014), and the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III and was co-financed by the European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for Research in Infectious Diseases (REIPI RD06/0008). Dr. Viasus is the recipient of a research grant from the Institut d'Investigació

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Cited by (64)

Risk factors for nosocomial infection among hospitalised severe influenza A(H1N1)pdm09 patients
2018, Respiratory Medicine
Nosocomial infections following influenza are important causes of death, requiring early implementation of preventive measures, but predictors for nosocomial infection in the early stage remained undetermined. We aimed to determine risk factors that can help clinicians identify patients with high risk of nosocomial infection following influenza on admission.
Using a database prospectively collected through a Chinese national network for hospitalised severe influenza A(H1N1)pdm09 patients, we compared the characteristics on admission between patients with and without nosocomial infection.
A total of 2146 patients were enrolled in the final analysis with a median age of 36.0 years, male patients comprising 50.2% of the sample and 232 (10.8%) patients complicated with nosocomial infection. Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Staphylococcus aureus were the leading pathogens, and invasive fungal infection was found in 30 cases (12.9%). The in-hospital mortality was much higher in patients with nosocomial infection than those without (45.7% vs 11.8%, P < 0.001). Need for mechanical ventilation (OR: 3.336; 95% CI 2.362–4.712), sepsis (OR: 2.125; 95% CI 1.236–3.651), ICU admission on first day (OR: 2.074; 95% CI 1.425–3.019), lymphocytopenia (OR: 1.906; 95% CI 1.361–2.671), age > 65 years (OR: 1.83; 95% CI 1.04–3.21) and anaemia (OR: 1.39; 95% CI 1.39–2.79) were independently associated with nosocomial infection.
Need for mechanical ventilation, sepsis, ICU admission on first day, lymphocytopenia, older age and anaemia were independent risk factors that can help clinicians identify severe influenza A(H1N1)pdm09 patients at high risk of nosocomial infection.
Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial
2017, Antiviral Research
− Macrolides can ameliorate inflammation in respiratory diseases, providing clinical benefits. Data in influenza is lacking.
− A randomized, open-label, multicenter trial among adults hospitalized for laboratory-confirmed influenza was conducted. Study treatments of oseltamivir and azithromycin (500 mg/day), or oseltamivir alone, both for 5 days, were allocated at 1:1 ratio. The primary outcome was plasma cytokine/chemokine concentration change over time (Day 0–10); secondary outcomes were viral load and symptom score changes. Generalized Estimating Equation (GEE) models were used to analyze longitudinal data.
− Fifty patients were randomized to the oseltamivir-azithromycin or oseltamivir groups, with comparable baseline characteristics (age, 57 ± 18 years; A/H3N2, 70%), complications (72%), and viral load. Pro-inflammatory cytokines IL-6 (GEE: β −0.037, 95%CI-0.067,-0.007, P = 0.016; reduction from baseline −83.4% vs −59.5%), CXCL8/IL-8 (β −0.018, 95%CI-0.037,0.000, P = 0.056; −80.5% vs −58.0%), IL-17 (β −0.064, 95%CI-0.117,-0.012, P = 0.015; −74.0% vs −34.3%), CXCL9/MIG (β −0.010, 95%CI-0.020,0.000, P = 0.043; −71.3% vs −56.0%), sTNFR-1, IL-18, and CRP declined faster in the oseltamivir-azithromycin group. There was a trend toward faster symptom resolution (β −0.463, 95%CI-1.297,0.371). Viral RNA decline (P = 0.777) and culture-negativity rates were unaffected. Additional ex vivo studies confirmed reduced induction of IL-6 (P = 0.017) and CXCL8/IL-8 (P = 0.005) with azithromycin.
− We found significant anti-inflammatory effects with adjunctive macrolide treatment in adults with severe influenza infections. Virus control was unimpaired. Clinical benefits of a macrolide-containing regimen deserve further study.
[ClinicalTrials.gov NCT01779570]
Corticosteroids for the treatment of human infection with influenza virus: A systematic review and meta-analysis
2015, Clinical Microbiology and Infection
Citation Excerpt :
The studies were published between 2004 and February 2015. Four studies described the effects of corticosteroid treatment on H5N1 infection [10,20–22], 13 studies described H1N1 infection [1,3,6,11,14–16,23–28], one study described H7N9 infection [29], and one study described seasonal influenza and influenza A(H1N1)pdm09 virus infection [30]. Dexamethasone, methylprednisolone and hydrocortisone were the corticosteroids used for patients with influenza virus infection.
Administration of corticosteroids to patients affected by influenza virus, especially pandemic avian influenza virus, although relatively common, remains controversial. A systematic review and meta-analysis was performed to assess the impact of corticosteroid treatment on outcomes of patients with influenza virus infection. The PubMed, EMBASE, Web of Science and Cochrane Library databases were searched up to February, 2015. Studies comparing corticosteroid treatment with no corticosteroid treatment in patients with influenza virus infection were included. The primary outcomes assessed were the association of mortality and nosocomial infection with corticosteroid treatment. Two authors independently extracted the data. ORs and weighted mean differences (WMDs) were used to describe dichotomous data and continuous data, respectively. Nineteen studies with 4916 patients were included in this meta-analysis. The results showed that corticosteroid treatment was significantly associated with mortality (OR 1.98, 95% CI 1.62–2.43, p < 0.00001) and nosocomial infection (OR 3.16, 95% CI 2.09–4.78, p < 0.00001). The durations of mechanical ventilation (WMD 3.82, 95% CI 1.49–6.15, p 0.001) and intensive-care unit stay (WMD 4.78, 95% CI 2.27–7.29, p 0.0002) were both markedly longer in the corticosteroid treatment group than in the control group. These findings suggest that routine steroid use may not be ideal for influenza virus infection. However, these results are derived from observational studies, with some important biases. They should be examined in future sufficiently powered randomized trials.
Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: A systematic review and meta-analysis
2020, CMAJ
Citation Excerpt :
Les données pour l’influenza provenant de 11 études de cohorte43-45,47,52,55,57-59,61,68 portant sur 8530 patients avec des estimations ajustées pour le risque de mortalité suggèrent que les corticostéroïdes pourraient accroître le risque de mortalité (rapport de cotes 1,70, IC de 95 % 1,31–2,21, DM 6,1 % plus élevé, données de faible qualité pour l’influenza et considérées comme très faible pour la COVID-19 en raison des données indirectes) (tableau 6, figure 4). Des données de très faible qualité pour l’influenza avec les considérations supplémentaires en raison des données indirectes qui proviennent d’études de cohorte ne comportant pas d’analyses ajustées ont soulevé la possibilité que les corticostéroïdes augmentent le risque de surinfection (rapport de cotes 2,74, IC de 95 % 1,51–4,95)43,44,47,52,55,57,65 et le nombre de patients nécessitant une ventilation mécanique (rapport de cotes 5,54, IC de 95 % 1,83–16,80) 52,57,59,61 (tableau 6). En tout, 13 ERC71-83 portant sur 2034 patients atteints d’une PEH se sont intéressés à plusieurs paramètres importants d’efficacité.
Il existe très peu de données directes sur l’administration de corticostéroïdes aux patients atteints de la maladie à coronavirus 2019 (COVID-19). Les données indirectes sur des maladies associées devront donc guider les conclusions quant aux bénéfices et aux préjudices associés à cette pratique. Dans le but d’appuyer la rédaction d’une ligne directrice sur la prise en charge de la COVID-19, nous avons réalisé des revues systématiques sur les effets des corticostéroïdes dans le traitement de la COVID-19 et de maladies respiratoires aiguës sévères associées.
Dans des bases de données biomédicales chinoises et internationales et des sources de prépublications, nous avons cherché les essais randomisés et contrôlés (ERC) et les études d’observation comparant des patients atteints de la COVID-19, du syndrome respiratoire aigu sévère (SRAS) ou du syndrome respiratoire du Moyen-Orient (SRMO) ayant reçu des corticostéroïdes à des patients semblables n’ayant pas reçu ce type de médicaments. Pour le syndrome de détresse respiratoire aiguë (SDRA), l’influenza et la pneumonie extrahospitalière (PEH), nous avons mis à jour les revues systématiques rigoureuses les plus récentes. Nous avons réalisé des méta-analyses à effets aléatoires pour cerner les risques relatifs, puis nous avons utilisé le risque de référence des patients atteints de la COVID-19 pour calculer les effets absolus.
Pour le SDRA, selon 1 petite étude de cohorte sur des patients atteints de la COVID-19 et 7 ERC sur des patients atteints d’une autre maladie (risque relatif : 0,72, intervalle de confiance [IC] de 95 % 0,55–0,93, différence entre les moyennes [DM] 17,3 % plus faible, données de faible qualité), les corticostéroïdes pourraient réduire le risque de mortalité. Chez les patients atteints d’une forme grave de COVID-19 sans SDRA, 2 études d’observation ont généré des données directes de très faible qualité montrant une augmentation du risque de mortalité avec l’administration de corticostéroïdes (rapport de risques 2,30, IC de 95 % 1,00–5,29, DM 11,9 % plus élevé). C’est aussi le cas de données observationnelles sur l’influenza. Des données observationnelles de très faible qualité sur le SRAS et le SRMO montrent peu ou pas de réduction dans le risque de mortalité. Des essais randomisés et contrôlés sur la PEH suggèrent que les corticostéroïdes pourraient réduire le risque de mortalité (risque relatif 0,70, IC de 95 % 0,50–0,98, DM 3,1 % plus faible, données de très faible qualité), et augmenter le risque d’hyperglycémie.
Les corticostéroïdes pourraient réduire le risque de mortalité pour les patients atteints de la COVID-19 avec SDRA. Pour les patients atteints d’une forme grave de COVID-19 sans SDRA, les données sur les bénéfices provenant de différentes sources sont incohérentes et de très faible qualité.
Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis
2020, CMAJ
Citation Excerpt :
Evidence in patients with influenza from 11 cohort studies43-45,47,52,55,57-59,61,68 including 8530 patients with adjusted effect estimates for mortality suggests that corticosteroids may increase mortality (OR 1.70, 95% CI 1.31 to 2.21, MD 6.1% higher; low-quality evidence for influenza rated down to very low for indirectness) (Table 6, Figure 4). Very low-quality evidence for influenza with additional consideration of indirectness when applied to COVID-19 from cohort studies that failed to conduct an adjusted analysis raised the possibility that corticosteroids may increase the rate of superinfection (OR 2.74, 95% CI 1.51 to 4.95)43,44,47,52,55,57,65 and increase the number of patients requiring mechanical ventilation (OR 5.54, 95% CI 1.83 to 16.80)52,57,59,61 (Table 6). Thirteen RCTs71-83 including 2034 patients with CAP addressed a number of important efficacy outcomes.
Very little direct evidence exists on use of corticosteroids in patients with coronavirus disease 2019 (COVID-19). Indirect evidence from related conditions must therefore inform inferences regarding benefits and harms. To support a guideline for managing COVID-19, we conducted systematic reviews examining the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses.
We searched standard international and Chinese biomedical literature databases and prepublication sources for randomized controlled trials (RCTs) and observational studies comparing corticosteroids versus no corticosteroids in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). For acute respiratory distress syndrome (ARDS), influenza and community-acquired pneumonia (CAP), we updated the most recent rigorous systematic review. We conducted random-effects meta-analyses to pool relative risks and then used baseline risk in patients with COVID-19 to generate absolute effects.
In ARDS, according to 1 small cohort study in patients with COVID-19 and 7 RCTs in non–COVID-19 populations (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.55 to 0.93, mean difference 17.3% fewer; low-quality evidence), corticosteroids may reduce mortality. In patients with severe COVID-19 but without ARDS, direct evidence from 2 observational studies provided very low-quality evidence of an increase in mortality with corticosteroids (hazard ratio [HR] 2.30, 95% CI 1.00 to 5.29, mean difference 11.9% more), as did observational data from influenza studies. Observational data from SARS and MERS studies provided very low-quality evidence of a small or no reduction in mortality. Randomized controlled trials in CAP suggest that corticosteroids may reduce mortality (RR 0.70, 95% CI 0.50 to 0.98, 3.1% lower; very low-quality evidence), and may increase hyperglycemia.
Corticosteroids may reduce mortality for patients with COVID-19 and ARDS. For patients with severe COVID-19 but without ARDS, evidence regarding benefit from different bodies of evidence is inconsistent and of very low quality.
Statins and influenza mortality: systematic review and meta-analysis
2022, Revista Chilena de Infectologia

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Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia

Summary

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Study design and patients

Results

Discussion

Acknowledgments

Influenza pathogenesis: lessons learned from animal studies with H5N1, H1N1 Spanish, and pandemic H1N1 2009 influenza

Crit Care Med

Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza

Crit Care

Delayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 2009 influenza virus infection

Clin Infect Dis

Macrolides for the treatment of severe respiratory illness caused by novel H1N1 swine influenza viral strains

J Infect Developing Countries

Pandemic influenza: a potential role for statins in treatment and prophylaxis

Clin Infect Dis

Cytokine profiles induced by the novel swine-origin influenza A/H1N1 virus: implications for treatment strategies

J Infect Dis

Steroid use in acute lung injury/acute respiratory distress syndrome: what about the acute lung injury from H1N1?

Crit Care Med

A new method of classifying prognostic comorbidity in longitudinal studies: development and validation

J Chronic Dis

A prediction rule to identify low-risk patients with community-acquired pneumonia

N Engl J Med

Time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines

J Am Med Assoc

Relaxing the rule of ten events per variable in logistic and Cox regression

Am J Epidemiol

The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial

Intensive Care Med

Effects of glucocorticoids in ventilated piglets with severe pneumonia

Eur Respir J