Latest developments in early diagnosis and specific treatment of severe influenza infection

Abstract

Influenza pandemics are unpredictable recurrent events with global health, economic, and social consequences. The objective of this review is to provide an update on the latest developments in early diagnosis and specific treatment of the disease and its complications, particularly with regard to respiratory organ failure. Despite advances in treatment, the rate of mortality in the intensive care unit remains approximately 30%. Therefore, early identification of potentially severe viral pneumonia is extremely important to optimize treatment in these patients. The pathogenesis of influenza virus infection depends on viral virulence and host response. Thus, in some patients, it is associated with an excessive systemic response mediated by an authentic cytokine storm. This process leads to severe primary pneumonia and acute respiratory distress syndrome. Initial prognostication in the emergency department based on comorbidities, vital signs, and biomarkers (e.g., procalcitonin, ferritin, human leukocyte antigen-DR, mid-regional proadrenomedullin, and lactate) is important. Identification of these biomarkers on admission may facilitate clinical decision-making to determine early admission to the hospital or the intensive care unit. These decisions are reached considering pathophysiological circumstances that are associated with a poor prognosis (e.g., bacterial co-infection, hyperinflammation, immune paralysis, severe endothelial damage, organ dysfunction, and septic shock). Moreover, early implementation is important to increase treatment efficacy. Based on a limited level of evidence, all current guidelines recommend using oseltamivir in this setting. The possibility of drug resistance should also be considered. Alternative options include other antiviral drugs and combination therapies with monoclonal antibodies. Importantly, it is not recommended to use corticosteroids in the initial treatment of these patients. Furthermore, the implementation of supportive measures for respiratory failure is essential. Current recommendations are limited, heterogeneous, and not regularly updated. Early intubation and mechanical ventilation is the basic treatment for patients with severe respiratory failure. Prone ventilation should be promptly performed in patients with acute respiratory distress syndrome, while early tracheostomy should be considered in case of planned prolonged mechanical ventilation. Clinical trials on antiviral treatment and respiratory support measures specifically for these patients, as well as specific recommendations for different at-risk populations, are necessary to improve outcomes.

Keywords: Acute respiratory distress syndrome; Influenza; Intensive care unit admission; Pandemic; Respiratory failure.

Figure 1

Schematic of the structure of the influenza A virion. NP: Nucleoprotein.

Figure 2

Key events in the immunopathology of influenza sepsis (adapted from Rubio et al.’s study^[18]with permission from the authors).

Figure 3

Immunophenotype groups in patients with influenza A H1N1pdm09. Diagram of the four immunophenotypes according to ferritin levels and HLA-DR expression. An increase in mortality is observed in groups with immunoparalysis (ID and HI + ID) (adapted from Valenzuela-Méndez et al.’s study^[34] with permission from the authors). HI: Hyperinflammation; HLA-DR: Human leukocyte antigen-DR; ICU: Intensive care unit; ID: Immunocompromised; MFI: Median fluorescence intensity.

Figure 4

Algorithms for deciding the destination of patients with severe influenza in the Emergency department by assessing risk factors, clinical assessment with rapid laboratory markers (PCT, ferritin, HLA-DR, MR-proADM, and lactate), and clinical scores (SOFA and qSOFA). HLA-DR: Human leukocyte antigen-DR; ICU: Intensive care unit; MR-proADM: Mid-regional proadrenomedullin; PCT: Procalcitonin; qSOFA: Quick Sequential Organ Failure Assessment Score; SOFA: Sequential Organ Failure Assessment Score.

Figure 5

Sequence of inflammatory activation due to IAV infection and its evolution into pneumonia and/or ARDS. (1) Possibility of identifying biomarkers of severity in IAV infection. (2) Conventional treatment with antivirals, as well as respiratory and hemodynamic support. Possibility of new perspectives of treatment modulating the inflammatory response, generally or specifically, or the administration of monoclonal antibodies (adapted from Valenzuela-Sánchez et al.’s study^[99]with permission from the authors). ARDS: Acute respiratory distress syndrome; CRP: C-reactive protein; ECMO: Extracorporeal membrane oxygenation; HA: Hemagglutinin; IAV: Influenza A virus; IL: Interleukin; MR-proADM: Mid-regional proadrenomedullin; NADPH: Nicotinamide adenine dinucleotide phosphate; NF-κB: Nuclear factor-κB; PCT: Procalcitonin; PMN: Polymorphonuclear neutrophil; PRRs: Pattern recognition receptors; RIG1: Retinoid-inducible gene 1; TLR7: Toll-like receptor 7; TNF: Tumor necrosis factor.