The results of our study showed that pulmonary bacterial coinfection occurred in 27% (32 /117) of patients with severe influenza pneumonitis. Those with bacterial coinfection had higher severity and longer ICU stay. Diabetes mellitus and liver cirrhosis were the independent risk factors for bacterial coinfection in patients with severe influenza pneumonitis. We also demonstrated that 19% (22/117) of patients with severe influenza pneumonitis had secondary bacterial pneumonia during the course of hospitalization. Those with secondary bacterial pneumonia had higher severity and longer ICU and hospital stay.
Unlike previous studies that reported that S. pneumoniae was the most frequent cause of bacterial coinfection,[18–20] the most common coinfection pathogens identified in our study were K. pneumoniae (31.4%), followed by S. aureus (22.8%), S. pneumoniae (11.4%), and P. aeruginosa (11.4%). This result was similar to a previous report from Taiwan. The higher percentage of K. pneumoniae coinfection could be related to the higher rates of chronic diseases such as diabetes mellitus, COPD or liver cirrhosis in our patients. A previous study reported significant increases in the incidence of MRSA infections in the past decade, particularly community-associated MRSA (CA-MRSA). In the pandemic of coronavirus disease 2019 (COVID-19), MRSA was also the most common and important bacteria in coinfection. In our study, 22.8% of the identified isolates were S. aureus among patients with coinfection, and 75% of these isolates were MRSA. This finding of coinfection pathogens supports the Infectious Disease Society of America recommendations for broad-spectrum antibiotic coverage for influenza-related pneumonia, particularly to cover CA-MRSA in patients with influenza-related pneumonia.
In case of secondary bacterial pneumonia, A. baumannii (28%) was the most often identified bacterium, followed by S. aureus (25%) and K. pneumoniae (17%). S. pneumoniae was not detected among secondary infection. Meanwhile, 66.7% of the S. aureus isolated were MRSA. Other drug-resistant specimens were also detected in patients with secondary infection (MDRAB 13%, MHT-positive K. pneumoniae 8%, and CRPA strain 8%). Those drug-resistant organisms should be covered by empiric antibiotic therapy if nosocomial pneumonia was suspected in these patients.
The risk factors including clinical symptoms, medical disease history, laboratory tests, and complications possibly contributed to poor patient outcomes after influenza virus infection remain to be elucidated. Understanding the risk of bacterial coinfection and secondary bacterial pneumonia and the distribution of variable pathogens in patients with influenza in the ICU can help physicians choose the appropriate antibiotics to minimize patient morbidity and mortality as well as prevent the individual and societal risks of using unnecessary antibiotics. Consistent with previous studies,[25–28] our study found that liver cirrhosis (OR: 4.673; 95% CI: 1.224–17.848) and diabetes mellitus (OR: 2.572; 95% CI: 1.117–5.919) were independent predictors of pulmonary bacterial coinfection in patients with severe influenza pneumonitis. Previous studies have described that cellular immune response was decreased, whereas antibody production was intact, in patients with advanced liver cirrhosis, and IFN-γ response was relatively poor. In addition, influenza virus itself can cause hepatitis, and influenza-induced toxic metabolites and proinflammatory cytokines such as TNF-α, IL-1, and IL-6 might contribute to hepatic damage[30, 31]. On the other hand, neutrophil chemotaxis and adherence to intracellular bactericidal activity, opsonization, vascular endothelium, phagocytosis, and cell-mediated immunity are all deteriorated in diabetic patients with hyperglycemia.[32, 33] Therefore, patients with liver cirrhosis and diabetes mellitus can have an immunosuppression status due to viral and bacterial infections, resulting in adverse complications and increasing the overall mortality. Therefore, influenza vaccine should be recommended to cirrhotic and diabetic patients.
These 117 critically ill patients with laboratory-confirmed influenza pneumonitis and were admitted to the medical ICU in the present study, had the 28-day mortality and in-hospital mortality rates being 15.4% and 21.3%, respectively. This result was similar to that of a previous study involving 444 adult hospitalized patients with influenza in the United States. A mortality rate of 20.6% had also been reported in a prospective multicenter observational cohort study of 2,059 patients admitted to ICUs for influenza infection.
Previous studies have mentioned that community-acquired bacterial coinfection can predict severity and mortality in patients admitted with influenza-associated pneumonia. Our study demonstrated that compared with patients without coinfection, those diagnosed with bacterial coinfection with had a significantly higher severity (higher APACHE II score) and longer ICU stay, but there was no significant difference in the duration of mechanical ventilation, length of hospital stay or mortality rate. The rate of mortality was similar to a previous report, which may be related to the increasing recognition of influenza, so that the intensivist could provide more optimal care in the ICU.
A higher mortality was reported in patients with nosocomial infections among those hospitalized with severe influenza A. Our research found the ICU stay and hospital stay were significantly longer in this patient group. Longer period of mechanical ventilation and higher mortality (21.4 vs. 9.6 days, P = 0.055 and 31.8% vs. 18.9%, P = 0.183, respectively) were also found in patients with secondary bacterial infection, although the difference had no statistical significance. This study provides data to clinicians to recognize that secondary bacterial infection is a contributor for increased morbidity and mortality in patients with severe influenza pneumonitis. The statistical insignificance could be related to the small case numbers in this study.
This study has some potential limitations. First, given the retrospective nature of the study, we did not collect information on previous influenza or pneumococcal vaccination. The impact of previous influenza vaccination could not be evaluated in this study. Second, due to the small case number, the statistical power might not be sufficient to assess the risk factors for mortality within this subpopulation. Third, the study population consisted of adult patients; therefore, the results cannot be generalized to pediatric patients. The strengths of this study include a detailed description of medical disease information at presentation and the entire bacterial specimen data of critically ill patients with influenza. We have also emphasized the key factors associated with bacterial coinfection and secondary bacterial infection in critically ill influenza patients and provided data to physicians to select the appropriate empiric antibiotics to minimize patient morbidity and mortality.