In a study involving 444 adult patients with influenza in hospitals in the United States, the mortality rate was 20.9% . Furthermore, a mortality rate of 20.6% was reported by Francisco et al. in their study of 2059 patients admitted to intensive care units for influenza infection . In our study, a mortality rate as high as 40% was found in 102 critically ill adult patients with influenza. However, which variables can predict poor patient outcomes after influenza virus infection remain to be elucidated. In the present study, our dataset included clinical signs and symptoms and laboratory results at presentation and the entire course of hospitalization as well as complications during the clinical course. We determined which demographic, clinical, and laboratory findings were associated with death that could help clinicians deliver timely sufficient treatment to critically ill influenza patients. Our results underscore that high blood lactate levels, ARDS, acute kidney injury, and gastrointestinal bleeding were independent risk factors of mortality in critically ill influenza patients.
High blood lactate levels indicate tissue hypoxia due to increased lactate generation via anaerobic glycolysis . High blood lactate levels have been correlated with poor outcomes in patients with bacterial sepsis and septic shock . In the present study, high blood lactate levels were found to be significantly and independently associated with fatal outcomes in critically ill influenza patients. In addition, non-survivors had a significantly higher prevalence of acute kidney injury and gastrointestinal bleeding, and received ECMO treatment in our series. Importantly, acute kidney injury and gastrointestinal bleeding have been shown to be independent risk factors of mortality. We believe that these complications are caused by clinicians’ lack of awareness of early detection of organ hypoperfusion. As patients in early phases of hypoperfusion do not always show obvious clinical signs, blood lactate level may be an important marker for this disorder. Thus, timely recognition of organ hypoperfusion and initiation of effective volume replacement to reverse tissue hypoxia are critical steps in preventing mortality and morbidity. Notably, the median time interval from patient arrival to measurement of highest blood lactate was 4 days in non-survivors in our series. Further, the median time from illness onset to fatality was 18.5 days. This finding indicates that blood lactate levels can be a useful early marker assisting clinicians in predicting the outcomes in critically ill influenza patients.
ARDS is a lethal complication of influenza infection . Ortiz et al. estimated that the incidence of influenza-associated acute respiratory failure was 2.7 events per 100,000 person-years . In a study of 58 patients with ARDS, 28 (48.2%) were due to influenza virus infection, and 32.1% of the patients with influenza-associated ARDS received ECMO treatment . Davies et al. reported that the incidence of pdm09 A/H1-associated ARDS sufficient to warrant consideration of ECMO was estimated at 2.6 cases per million population . ARDS is an independent risk factor for hospital mortality in critically ill influenza patients, and the mortality rate can be as high as 52% . The present study results are consistent with previous findings wherein 97% of critically ill influenza patients developed acute respiratory failure with a median time of 4 days between illness onset and respiratory failure, and 51% of them subsequently developed ARDS during their clinical course. In addition, approximately one-third of the patients with influenza-associated ARDS required ECMO for profound hypoxemic respiratory failure. Our study highlights that severe oxygenation failure occurred rapidly after hospital admission, and that clinicians should not delay delivering appropriate rescue therapies as well as deploying intensive care unit resources to meet this treatment requirement, particularly during the influenza epidemic.
In the present study, we established a simple event-associated algorithm including blood lactate level and ARDS for timely detection of critically ill influenza patients who are at greater risk of mortality. Notably, critically ill influenza patients without ARDS but with a blood lactate concentration of 33 mg/dL had an in-hospital mortality of 47.1%, and more importantly, the mortality rate increased to 75% for those with high blood lactate (≥ 33 mg/dL) and developed ARDS. In contrast, only 7.7% of critically ill influenza patients without ARDS and with normal blood lactate levels died. Considering the high mortality rate among critically ill influenza patients, this event-based algorithm could aid in the timely decision-making process and provision of prompt intensive care for patients with potentially fatal outcomes, particularly in resource-limited areas; some key laboratory tests such as blood lactate might be of greater value than others when allocating limited healthcare resources.
Previous studies have shown that early administration of an antiviral agent is associated with a shorter duration and reduced severity of illness [14, 15, 16]. Greater benefits were shown with early treatment initiated within 2 days after the onset of illness [30, 31, 32]. In our study, the median time from illness onset to hospital presentation was 3 days and more than two-thirds of the patients received delayed (48 h after illness onset) antiviral treatment. Although the provision of antiviral therapy between survivors and non-survivors did not differ significantly in our series, the importance of early treatment with antivirals in critically ill influenza patients cannot be overemphasized.
In our study, bacteremia was detected in 17 critically ill adult patients. Importantly, 5 of them acquired bacteremia within 48 h after hospitalization, and in 3 cases, the infection was caused by Staphylococcus aureus. A report of the 2009–2010 influenza pandemic among critically ill children revealed that nearly 5% of the patients had bacteremia within 72 hours and Staphylococcus aureus was the most frequently isolated bacterium, which contributed to the death rate in the current pandemic . In a study of 32 influenza-positive patients (including pediatric and adult patients), poor outcomes were found among patients who were co-infected with influenza viruses and Staphylococcus aureus . Although we were unable to conclude whether or not initiating timely additional antimicrobial treatment in critically ill influenza patients led to better clinical outcomes, our findings and previous reports underscore that Staphylococcus aureus remains the most important cause of bacterial coinfection in pediatric and adult influenza patients.
Invasive pulmonary Aspergillus as a coinfection in patients with severe influenza has been described [35, 36, 37]. In a cohort study involving 7 intensive care units over a period of 7 influenza seasons showed that influenza and the use of corticosteroids were independent risk factors for invasive aspergillosis . In the present study, invasive pulmonary aspergillosis was confirmed in 2 deceased influenza patients with high galactomannan index in bronchoalveolar lavage fluid. This finding emphasizes that clinicians should be aware of the risk of invasive aspergillosis in critically ill influenza patients, particularly immunocompromised patients or those receiving corticosteroids. Further studies are needed to understand the incidence, risk factors, and clinical features of invasive pulmonary aspergillosis in influenza patients.
This study has several potential limitations. First, given the retrospective nature of the study, data on vaccination status, including pneumococcus and influenza, were not collected. Second, the study population comprised adult patients; therefore, the results cannot be generalized to pediatric patients. However, the strengths of this study include a detailed description of clinical and laboratory information at presentation and the entire hospitalization course critically ill patients with influenza. We highlighted the key factors associated with poor outcomes for critically ill influenza patients and established decision-making algorithms that can take advantage of simple clinical and laboratory evaluations.