Background
The mutation rate of influenza A virus is the highest among the three reported subtypes of human influenza virus (A, B, and C) [
1]. Large-scale human-to-human transmission of influenza A virus can occur biannually, in winter and spring. Outbreaks of influenza A virus infection in hospitalized patients have been reported in a variety of clinical settings including neonatal intensive care units [
2], geriatric wards [
3], and hematology units [
4]. Hospital-acquired influenza A attacks hospitalized patients with a primary disease and results in additional treatment burdens and adverse health consequences.
Hospital-acquired influenza A may be associated with a poor prognosis. In Germany, a case fatality rate of 9% was mainly associated with influenza virus A (H1N1) pdm09 [
5], and in Sweden, a hospital-acquired influenza A with a case fatality rate of 9.6% has been reported [
6]. Moreover, hospital-acquired influenza A has been reported to be an independent factor associated with mortality among patients admitted to an intensive care unit (ICU) [
7].
Hospitals are semi-closed settings and hospitalized patients are in close contact with each other. Patients with influenza A in the incubation period can be asymptomatic sources of infection [
8]. The incubation period may be as long as 7 days [
9], which makes the prevention and control of influenza A among hospitalized patients a major challenge. Therefore, the early recognition of patients with a high risk of hospital-acquired influenza A can play an important role in the prevention of influenza A outbreaks among hospitalized patients.
Although the clinical and epidemiological features of hospital-acquired influenza A are well-documented [
10,
11], there have been few studies on its risk factors. While other published studies chose community-acquired influenza A cases as controls [
7,
12], our study selected controls that were hospitalized in the same department and during the same time period without acquiring the infection, and thus matching cases and controls more reliably.
This study aimed to identify the risk factors for hospital-acquired influenza A, so that vulnerable individuals could be identified at an early stage.
Discussion
To the best of our knowledge, this is the first retrospective matched case-control study of risk factors for hospital-acquired influenza A that included all the different departments of a hospital over a single full influenza A season. This is the first study to identify lymphocytopenia, hypoalbuminemia, and pleural effusion as independent risk factors for hospital-acquired influenza A.
In China, according to the overview of epidemic situation of statutory infectious diseases provided by the National Health Commission, the number of influenza (A, B, and C) cases from January 2019 to April 2019 was 1.575 million which is considerably more than the 0.768 million cases reported for the 2018 year [
16,
17]. Influenza weekly statistics released by the Chinese National Influenza Center showed that in the first, fifth, and ninth week of 2019, influenza A virus was the main pathogen, accounting for 99.5, 98.1, and 89.9% of influenza cases in the Northern Provinces of China, respectively [
18]. In our study, hospital-acquired influenza A cases occurred mainly in January and February 2019. Furthermore, according to the influenza weekly, H1N1 subtype accounted for 92.7 and 86.9% of influenza A in the first and fifth week of 2019 in Northern China, respectively [
18].
Our study has two main strengths. First, with a strict case definition and a rigorous paired design, we consider that our comparative analysis is more reliable than those of previous studies [
7,
12]. Second, hospital-acquired influenza A cases were selected from all the different departments of the hospital in a single influenza A season, indicating that hospital-acquired infection was caused by identical or similar influenza A virus strains, which ensured the comparability and homogeneity of clinical data.
Approximately 23% of the influenza cases diagnosed in our study were classified as hospital-acquired. This large proportion of cases may be because of the large increase in the number of influenza cases nationwide in China in early 2019 compared with previous years. Studies conducted in other countries have had similar findings. In a tertiary care hospital in France, during the 2016–2017 influenza A season, 25% of hospitalized patients with influenza A were considered to be hospital-acquired [
12]. A German university hospital reported 24% hospital-acquired infection cases in the 2012–2013 influenza season and 20% in the 2013–2014 season [
5]. However, a lower proportion of hospital-acquired cases have been observed in other studies. In the UK, during the 2009 H1N1 pandemic, 2% of hospitalized cases with influenza A were considered hospital-acquired [
19]. In an epidemiological study based on the data of six influenza seasons from 2010 to 2011 to 2015–2016 in Spain, of the hospitalized patients with confirmed severe influenza, 5.6% were classified as hospital-acquired [
20].
This variability in the prevalence of hospital-acquired influenza A can be attributed to variations in study design and differences between regions and strains of virus. Currently, there is no consensus with respect to the criteria required for declaring an influenza outbreak in a hospital. According to some studies, a hospital-acquired influenza outbreak is defined by an increase in cases of hospital-acquired influenza in a short time and limited space [
21,
22].
The suspected patients from the Nephrology and Geriatric Departments had a higher positive rate of diagnosis than the average of the hospital. Most patients in the Nephrology Department had chronic kidney diseases, leading to a range of immune system defects [
23] such as decreased chemotaxis and phagocytosis of monocyte/macrophage, B-cell lymphopenia, and depressed CD4
+ and CD8
+ T cell responses [
24]. Therefore, patients in the Nephrology Department were more vulnerable to the morbidity and mortality associated with influenza infections [
25]. Corticosteroids are commonly used drugs in the Nephrology Department and recent research has shown that corticosteroid use can enhance the replication of respiratory viruses [
26]. However, corticosteroid use was not a significant risk factor for hospital-acquired influenza A in our study, probably because we matched cases with controls from the same department, and thus the cases and controls were treated with similar medications. It has been reported that age > 65 years was a risk factor for influenza [
27]. Thus, suspected patients in the Geriatric Department in a poor basic physical condition can be more likely to test positive for influenza A. During annual seasonal influenza A epidemics, it is recommended that the Nephrology and Geriatric Departments pay more attention to disease prevention and diagnosis.
Due to death and loss of follow-up, we were unable to ascertain the vaccination status of a few patients. However, the vaccination uptake among both the hospital-acquired influenza A cases and the controls was only 1.3 and 2.4%, respectively, a difference that was not statistically significant. The coverage of influenza vaccine in the overall Chinese population was reported to be 0.8–2.2% during 2004 to 2014 [
28]. Furthermore, in 2017, of the 379 adults aged ≥60 years who were interviewed in a developed city in eastern China, only 0.8% reported receiving the influenza vaccine in the previous year [
29]. Currently, self-paid vaccination, unawareness of the need, and few recommendations from medical staff contribute to the low vaccine coverage. By contrast, the vaccination coverage among older people in England, France and Germany reached 73, 49 and 37% respectively during the 2014–2015 season [
30].
There are several reasons why hospital-acquired viral infections are less likely to be reported than hospital-acquired bacterial infections, including historical attention to bacterial infection [
31], difficulties in diagnosis of viral infections, and limited availability of antiviral drugs [
11]. Droplet precautions with single room isolation, as an important infection control procedure, are required for all suspected or confirmed cases. This consumes a vast amount of medical resources, creating challenges in the prevention and control of hospital-acquired influenza A. Notably, our study showed that hospital-acquired influenza A carried a considerable risk of death and prolonged hospital stay compared to the control group.
Our findings indicated that the Geriatric and Neurology Department had the highest number of hospital-acquired influenza A cases, followed by the Hematology and Cardiac Surgery Departments. During the influenza season, patients who underwent cardiac surgery were more likely to develop acute respiratory distress syndrome (ARDS) [
32]. In this study, all patients from the Cardiac Surgery Department had undergone surgery before they acquired influenza A, however we were unable to determine whether cardiac surgery increases the risk of influenza A. This question requires further investigation.
Lymphopenia is common among patients with influenza A [
33] and is associated with poor outcomes [
34]. Influenza viral replication is initially controlled by innate immunity and thereafter adaptive immune responses (T cells and antibody-producing B cells), lead to viral clearance and host recovery [
35]. This may explain the frequent outbreaks of influenza A in Hematology Departments that have occurred over many years [
4,
36,
37].
Hypoalbuminemia is the result of the combined effect of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure [
38]. Hypoalbuminemia is frequently observed in hospitalized patients, therefore early detection of vulnerable individuals is essential for implementation of infection control. While we do not recommend albumin supplementation for patients with hypoalbuminemia for the prevention of influenza A, we recommend that measures such as droplet precautions with single room isolation be mandatory.
Pleural effusion, a radiographic finding, can be caused by hypoalbuminemia, pleural infections, heart and kidney failure, pulmonary embolism or malignancy. We did not quantify the amount of effusion or differentiate between single-sided and bilateral effusions, but used it as a qualitative diagnosis. Two studies from Taiwan reported that in pediatric influenza patients, radiographically-confirmed pleural effusion on admission was significantly associated with a severe infection that required intensive care [
39,
40]. Having a pleural effusion might make patients more vulnerable to the influenza A virus through an unknown mechanism.
There are some limitations to our study. We were not able to meet the requirement for the design that every hospital-acquired influenza A patient should be matched with a ideal control case, who had been hospitalized for 7 days or more in the same room on the date when the paired case acquired influenza. To ensure a sufficient sample size, we were only able to match the same department, but not the same room. This may have reduced the comparability of the two groups. However, two matched patients from the same department were exposed to the same aerosol environment, which played an important role in the spread of the infection. In addition, a relatively stringent definition of hospital-acquired influenza A was adopted, therefore some cases may have been missed and the true risk of acquiring influenza A in the hospital, underestimated. Finally, the clinical data from patients hospitalized for more than 7 days because of severe primary diseases may have exaggerated the impact of hospital-acquired infections, thus the clinical characteristics of hospital-acquired influenza A may be overstated.
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