Annual Update in Intensive Care and Emergency Medicine 2017

Annual Update in Intensive Care and Emergency Medicine 2017

The Annual Update compiles reviews of the most recent developments in experimental and clinical intensive care and emergency medicine research and practice in one comprehensive reference book. The chapters are written by well recognized experts in these fields. The book is addressed to everyone involved in internal medicine, anesthesia, surgery, pediatrics, intensive care and emergency medicine.

Severe influenza infection is an important cause of acute lung injury. Although other respiratory viruses (e. g., respiratory syncytial virus, human metapneumovirus) canalso cause considerable pulmonary damage, influenza virus remains the main cause of respiratory failure in patients with suspected viral respiratory tract infection. In addition, influenza virus is the only respiratory virus that has caused four pandemics over the last 100 years, making it one of the most transmissible and virulent viruses in the world. Here, we review the pathogenesis, diagnosis, current management and future therapy of severe influenza infection.

Understanding the pathogenesis of severe influenza infection is the key to developing new therapeutic strategies. Although the basic process of a mild influenza infection is well understood, our understanding of how a mild illness progresses to a potentially lethal pulmonary infection remains poor. In this section, we will review recent advances in the immunopathology of severe influenza infection. Pulmonary epithelial cells are the first target of invasion by influenza virus. Like most cells, epithelial cells constitutionally upregulate the interferon pathway in response to infection by viruses. Types I and III interferon pathways are the natural defense mechanism against influenza virus. Upon infection, epithelial cells upregulate interferon regulatory factors (IRF), such as IRF-3 and IRF-7. This leads to transcription and translation of a downstream interferon pathway, which in turn produces a family of interferon-stimulated genes/proteins. This vast family of interferon-stimulated genes/proteins (> 300) provides a wide spectrum of anti-viral effects, ranging from inhibition of viral replication to sensing of influenza virus inside the host cells. This response is immediate and effective, making it a critical part of the innate immune response against influenza virus. Whilst essential, the interferon response alone is not sufficient to prevent virus replication in severely infected cases. Multiple subsets of immune cells (e. g., macrophages, dendritic cells and neutrophils) are required to mount an effective immune response. The failure of this immune response is the hallmark of severe infection, which is characterized by multiple defects in immune cell recruitment, activation or proliferation, as described below.
Alveolar macrophages are among the early responders to influenza virus. They phagocytose infected cells containing influenza virus and initiate other cells of innate and adaptive immunity. Failure of alveolar macrophages to mount an effective early response is associated with increased viral dissemination and increased morbidity/mortality. Neutrophils are also early responders in severe influenza infection. Similar to alveolar macrophages, failure of this early neutrophil response is a prominent feature of severe influenza infection. Paradoxically, an exuberant or inappropriately exaggerated neutrophil response is also a feature of severe influenza infection. For example, in severe H1N1 and H5N1 infection, the large influx of
neutrophils into the alveolar space is a classic feature [1] . During this massive neutrophil influx, the neutrophils release a large amount of cytokines, extracellular proteases and histones. This leads to a breakdown of the epithelial barrier, accumulation of reactive oxygen species (ROS), flooding of alveolar spaces by inflammatory fluid and increased barrier to oxygenation, all of which contribute to the clinical picture of acute lung injury commonly observed in patients with severe influenza infection.
Other immune cells are also involved in this early phase of infection (and contribute to pathogenesis). Monocytes, for example, traffic into the infected pulmonary tissue and participate in a pro-inflammatory response. Not surprisingly,inhibition of monocytes and preventing their subsequent participation in the proinflammatory response has been shown to decrease the extent of acute lung injury in animal models [2,3] . Pulmonary dendritic cells are another important immune cell subset that contributes to pathogenesis. In a murine model of influenza infection, pulmonary dendritic depletion increased macrophage recruitment and enhanced pro-inflammatory responses (tumor necrosis factor [TNF] -˛/interleukin [IL] -6 increased 5–35 fold) [4] . In another murine model, pulmonary dendritic cells induced
T-regulatory cell responses that suppressed antigen-specific CD8 cells, thereby preventing an effective immune response [5] . Hence, the pathogenic role of dendritic cells seems to be to cause a dysregulated immune response, which either causes excessive lung injury (by causing increased inflammation) or impairs the effective clearance of influenza virus (by limiting CD8 cell response)

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