Pro: the illegitimate crusade against corticosteroids for severe H1N1 pneumonia.
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ABSTRACT: Statins not only reduce levels of LDL-cholesterol, they counteract the inflammatory changes associated with acute coronary syndrome and improve survival. Similarly, in patients hospitalized with laboratory-confirmed seasonal influenza, statin treatment is associated with a 41% reduction in 30-day mortality. Most patients of any age who are at increased risk of influenza mortality have chronic low-grade inflammation characteristic of metabolic syndrome. Moreover, differences in the immune responses of children and adults seem responsible for the low mortality in children and high mortality in adults seen in the 1918 influenza pandemic and in other acute infectious and non-infectious conditions. These differences probably reflect human evolutionary development. Thus the host response to influenza seems to be the major determinant of outcome. Outpatient statins are associated with reductions in hospitalizations and deaths due to sepsis and pneumonia. Inpatient statins are also associated with reductions in short-term pneumonia mortality. Other immunomodulatory agents - ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), PPARγ and PPARα agonists (glitazones and fibrates) and AMPK agonists (metformin) - also reduce mortality in patients with pneumonia (ACEIs, ARBs) or in mouse models of influenza (PPARγ and AMPK agonists). In experimental studies, treatment has not increased virus replication. Thus effective management of influenza may not always require targeting the virus with vaccines or antiviral agents. Clinical investigators, not systems biologists, have been the first to suggest that immunomodulatory agents might be used to treat influenza patients, but randomized controlled trials will be needed to provide convincing evidence that they work. To guide the choice of which agent(s) to study, we need new types of laboratory research in animal models and clinical and epidemiological research in patients with critical illness. These studies will have crucial implications for global public health. During the 2009 H1N1 influenza pandemic, timely and affordable supplies of vaccines and antiviral agents were unavailable to more than 90% of the world's people. In contrast, statins and other immunomodulatory agents are currently produced as inexpensive generics, global supplies are huge, and they would be available to treat patients in any country with a basic health care system on the first pandemic day. Treatment with statins and other immunomodulatory agents represents a new approach to reducing mortality caused by seasonal and pandemic influenza. This article forms part of a symposium in Antiviral Research on ''Treatment of influenza: targeting the virus or the host.''Antiviral research 07/2013; · 3.61 Impact Factor
- American Journal of Respiratory and Critical Care Medicine 06/2012; 185(12):1261-5. · 11.04 Impact Factor
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ABSTRACT: Secondary bacterial pneumonia is a significant cause of morbidity and mortality during influenza, despite routine use of standard antibiotics. Antibiotic-induced immunopathology associated with bacterial cell wall lysis has been suggested to contribute to these poor outcomes. Using Streptococcus pneumoniae in a well-established murine model of secondary bacterial pneumonia (SBP) following influenza, we stratified disease severity based on pneumococcal load in the lungs via in vivo bioluminescence imaging. Ampicillin treatment cured mice with mild pneumonia but was ineffective against severely pneumonic mice, despite effective bacterial killing. Adjunctive dexamethasone therapy improved ampicillin-induced immunopathology and improved outcomes in mice with severe SBP. However, early dexamethasone therapy during primary influenza infection impaired lung adaptive immunity as manifest by increased viral titers, with an associated loss of its protective functions in SBP. These data support adjunctive clinical use of corticosteroids in severe cases of community-acquired pneumonia.The Journal of Infectious Diseases 11/2013; · 5.85 Impact Factor
Pro: The Illegitimate Crusade against Corticosteroids for
Severe H1N1 Pneumonia
In this issue of the Journal, two groups of authors, one from
France (pp. 1200–1206), one from South Korea (pp. 1207–1214),
reported increased mortality and increased hospital-acquired
infections with the use of corticosteroids in ICU patients with
severe H1N1 pneumonia (1, 2). Obviously one’s first impression
would be to abandon the use of corticosteroids in such patients.
We will demonstrate that nothing is wrong with using cortico-
steroids for treating H1N1-related severe pneumonia.
THERE IS A STRONG BIOLOGICAL RATIONALE
SUPPORTING THE USE OF CORTICOSTEROIDS
Acute lung injury following H1N1 influenza infection was
characterized by uncontrolled lung and systemic inflammation
(3). Autopsy findings demonstrated inflammation-induced dam-
ages rather than uncontrolled viral infection (4). Basically, three
distinct abnormalities can be found: classic exudative diffuse
alveolar damage, severe necrotizing bronchiolitis with extensive
and predominantly neutrophilic inflammation of bronchiolar
wall and lung parenchyma, and extensive diffuse alveolar
damage plus intense alveolar hemorrhage. These lesions are
caused by excessive host innate response with exaggerated
trafficking of macrophages and neutrophils (5). Subsequently,
huge amounts of highly cytotoxic mediators, such as proin-
flammatory cytokines, superoxide, reactive oxygen species, and
reactive nitrogen species, are abundantly released in the lung
parenchyma (6). Corticosteroids’ transrepression effects occur
within a few hours, resulting from physical sequestration in the
cytosol of nuclear transcription factors like NF-kB and AP-1, by
monomeric glucocorticoid–glucocorticoid receptor a (GGR)
complexes, preventing the reading of genes encoding for most
if not all proinflammatory mediators. Their transactivation
effects require a few days of exposure to a corticosteroid. After
conformational changes, the GGRa complex enters the nucleus
and up-regulates, via glucocorticoid-responsive elements, genes
encoding for regulators of termination of inflammation. Sub-
sequently, key antiinflammatory factors, including phagocytosis,
chemokinesis, and antioxidative processes, are activated. Thus,
corticosteroids reprogram rather than inhibit immune cells.
Corticosteroids induce specific activated, antiinflammatory
monocyte subtypes that migrate quickly to the inflamed tissues,
and prolong these cells survival via an A3 adenosine receptor–
triggered anti-apoptotic effect (7). Obviously, these molecular
mechanisms of action of glucocorticoids are appropriate to
counteract the uncontrolled inflammation that characterized
severe influenza pneumonia (Table 1). Then, unsurprisingly, in
a cotton rat model, in combination to neuraminidase inhibitor,
corticosteroids dose-dependently inhibited inflammatory cells
recruitment to the lung and expression of proinflammatory
mediators without affecting viral clearance (8).
CLINICAL EXPERIENCE IS INHOMOGENEOUS AND
QUALITY OF CLINICAL DATA AGAINST
CORTICOSTEROIDS IS UNRELIABLE
During the 2009 H1N1 pandemic, corticosteroids have been
broadly used, and their effects have been variously reported as
beneficial (9–11), unfavorable (1, 2), or neutral (12, 13). A recent
review has analyzed 22 studies reporting on treatment strategies
for patients with H1N1 from the 2009 pandemic (14). There were
0 randomized trials, 15 cohort studies of more than 10 patients,
and 7 case series, for a total of 3,020 patients (of whom 1,068
were ICU patients). Corticosteroids were used in 333 patients.
There was no evidence for increased mortality with corticoste-
roids. The two reports from France and South Korea (1, 2) share
the same flaws as all previous reports on this topic. Undoubtedly,
the only proper method for assessing the efficacy and safety of
any drug for any disease is a randomized, double-blind trial.
Registries and retrospective cohorts usually aim at describing the
natural history of a disease and not at investigating interventions.
Indeed, they cannot allow an adequate minimization of selection
and confusion biases in the evaluation of drug efficacy or safety,
even when based on propensity score analysis. In addition, there
are numerous examples of interventions found to be harmful in
cohort studies and not in subsequent randomized trials. Among
these interventions, the ‘‘story’’ of the pulmonary artery catheter
is likely one of the most popular. The provocative increased
mortality associated with the use of the Swan Ganz catheter
suggested by a large cohort using propensity-matched analysis
(15) was subsequently contradicted by several randomized trials
(16). Other examples included dopamine, epinephrine, albumin,
or synthetic colloids. Amazingly, in the ‘‘French’’ cohort, the
authors could also have concluded that the use of vasopressors
increased mortality in patients with severe H1N1 pneumonia (1).
Indeed, this treatment was also selected as an independent
predictor of death. Obviously, this is likely untrue, just as it is
for corticosteroids. Sophisticated statistical approaches such as
propensity score matching can only take into account measured
confounding factors, whereas randomized trials allow controlling
for both measured and unmeasured factors (17). Furthermore, in
settings with a high correlation between exposure and con-
founders, as in the case of corticosteroids and H1N1 pneumonia,
analyses based on propensity scores usually yielded exaggerated
levels of statistical significance (18). Therefore, propensity score–
based analysis does not resolve the traditional concern in
pharmacoepidemiology that patients who receive a drug differ
in disease severity or have other prognostic differences with
untreated patients (17). In addition, in the retrospective cohorts
reported in this issue of the Journal (1, 2) there was no control for
the experimental treatment (i.e., corticosteroids). Many patients
in these cohorts may have received corticosteroids for other
reasons than H1N1-induced acute lung injury or acute respiratory
distress syndrome (ARDS). Indeed, initiation of corticosteroids
was positively associated with hematologic malignancies, cancer,
or chronic obstructive pulmonary disease, and negatively associ-
ated with the absence of underlying disease (2). It was not clear
which type of corticosteroids was used (2), as the pharmacolog-
ical properties of different steroids are not equal. Timing of
Am J Respir Crit Care Med
Internet address: www.atsjournals.org
Vol 183. pp 1125–1128, 2011
initiation ranged from 22 days to 14 days, and the dose from 200
to 1,600 mg of hydrocortisone or equivalent (1). Finally, neither
the duration nor the weaning of corticosteroids was controlled.
Of note, after more than half a century of use of corticosteroids
for severe infections or ARDS, there is no single randomized trial
that has shown increased mortality or increased superinfection.
Moreover, in the ARDSnet trial of corticosteroids for persistent
ARDS, corticosteroids decreased the risk of superinfection and
sepsis (19). Likewise, in a recent multicenter trial in multiple
trauma, hydrocortisone therapy was associated with a dramatic
reduction in the onset of ventilator-associated pneumonia (20). In
sum, it would certainly be a great mistake to change practice on
the basis of retrospective data that are so markedly contrasting
with the current knowledge of the mechanisms of action of
corticosteroids and with their effects demonstrated in random-
ized trials in patients with all-cause ARDS or sepsis.
Author Disclosure: D.A. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript.
Djillali Annane, M.D., Ph.D.
Raymond Poincare ´ Hospital (AP-HP)
University of Versailles
Acknowledgment: The author thanks Professor Jean Marc Cavaillon, Pasteur
Institute, Paris, France, for his helpful contribution in the writing of this manuscript.
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TABLE 1. PUTATIVE MECHANISMS OF H1N1-INDUCED LUNG INJURY AND OF CORTICOSTEROIDS COUNTERBALANCING EFFECTS
Exaggerated Innate Immune Response to H1N1Effects of Corticosteroids
Increased trafficking of neutrophils and activated
monocytes to the lung
Promote a Th1-type response
Promote Th17-ype cells
Up-regulate expression of TLR-7 and NoD-like receptors/RIG-I
Overexpression of IL-1, IL-6, IL-8, IL-12p70
Overexpression of IL-15, IL-10
Overexpression of COX-II
Promote radical oxygen species and other oxidative processes
Induce breakdown of the capillary–alveolar barrier
Promote cytokine-triggered apoptosis of epithelial cells and pneumocytes I and II
Decreased neutrophil trafficking, reprogramming of monocytes to produce
antiinflammatory subtypes that migrates quickly to the inflamed lung
Induce a shift to a Th2 response
Inhibit Th17 cell production of cytokines
Down-regulate expression of TLR-7 and NoD-like receptors/RIG-I
Inhibit IL-1, IL-6, IL-8, IL-12p70
Unaltered regulation of IL-15, IL-10
Promote antioxidative processes
Protect the capillary–alveolar barrier
Prevent cytokine-triggered apoptosis of epithelial cells and pneumocytes I and II
Definition of abbreviations: COX 5 cyclooxygenase; NoD 5 nucleotide-binding domain–like receptor; RIG-1 5 retinoic acid–inducible gene (RIG)-I–like receptors;
TLR 5 Toll-like receptor.
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