It is well known that respiratory viral infections, especially influenza A virus infections, significantly increase the susceptibility of humans to bacteria. Histopathological evidence has confirmed that secondary pulmonary bacterial infections were the most important cause of death in patients during the 1918 and 2009 influenza pandemics [1-3]. However, why influenza is prone to secondary pulmonary bacterial infections is not fully understood to date; epidemiological data on the prevalence, types of infecting bacteria, risk factors, geographic characteristics, and population characteristics of secondary pulmonary bacterial infections in influenza are also scarce in large-scale clinical studies. Therefore, there is a lack of standardized methods for the surveillance and prevention of influenza-associated pulmonary bacterial infections. Yi Shi, Department of Respiratory Medicine, General Hospital of Nanjing Military Region I. Status of secondary bacterial infections after respiratory viral infections 1. Epidemiology In the early 19th century, the French physician R.T.H. Laennec first discovered that influenza patients were prone to secondary pulmonary bacterial infections [4]. 1918 saw the largest global outbreak of Spanish influenza, and according to conservative estimates, this influenza pandemic caused about 40-50 million deaths [5]. A retrospective analysis of all autopsies of patients who died from influenza at that time reported that more than 90% of a total of 8398 patients died from secondary bacterial lung infections [1].In 1918, antimicrobial drugs were not yet available, so the mortality rate of influenza secondary to bacterial lung infections was extremely high. However, after the introduction of antimicrobial drugs, secondary pulmonary bacterial infections remained the leading cause of death in influenza patients [1].During the 1957-1958 Asian influenza pandemic, one study found that 75% of patients who died from influenza had microbiological and histopathological examinations that confirmed secondary pulmonary bacterial infections [6].During the 2009 H1N1 influenza A pandemic, one study found that more than 50% of influenza deaths were confirmed by microbiological and pathological examination to be secondary to bacterial pneumonia [3]. A study by American scholars found that 43% of pediatric patients who died from influenza between April and August 2009 also had bacterial lung infections [7]. In addition to secondary bacterial infections, the incidence of mixed seasonal influenza and bacterial infections is extremely high [8]. Approximately 4% to 56% of adult influenza patients and 22% to 33% of pediatric influenza patients have mixed pulmonary bacterial infections [3,9-14].2. The current status of diagnosis of secondary bacterial infections is difficult to distinguish from secondary bacterial pneumonia from clinical and imaging features alone because influenza viruses also cause respiratory symptoms and pulmonary infiltrative shadows; combined with positive bacterial cultures of respiratory secretions yet to rule out colonization or contamination, and In addition to the widespread use of broad-spectrum antibacterial drugs, clinical microbiological tests are often difficult to clarify whether a patient has a secondary or combined bacterial lung infection, and likewise to identify the causative agent. As a result, the incidence of secondary or mixed bacterial infections in influenza may actually be underestimated. There is also a lack of epidemiological data on whether many patients with milder, outpatient influenza have secondary or co-infections with pulmonary bacteria. This leads to treatment difficulties, especially as irrational use of antimicrobial drugs is very common. Second, the mechanism of secondary bacterial infection following respiratory viral infection is not fully understood to date. Numerous studies have attempted to uncover the causes of secondary bacterial infections in order to find interventions and preventive measures.1. Airway epithelial disruption Influenza viruses replicate mainly in airway epithelial cells, disrupting the airway epithelial barrier and thus allowing bacteria to adhere to the airway mucosa and thus invade the lung parenchyma [15, 16]. Autopsies of patients who died from influenza in 1957-1958 confirmed that S. aureus could adhere to the disrupted airway mucosa [6]. Influenza disruption of the airway epithelium peaks 7 days after infection [17], which could explain why secondary bacterial infections usually occur about 1 week after influenza virus infection. However, subsequent animal studies have found that even if influenza virus does not disrupt the airway epithelial barrier, it still increases the susceptibility of mouse lungs to bacteria [18, 19]. Neuraminidase assists influenza virus infection of airway epithelial cells and is the most important invasion factor of influenza virus, but it was found that neuraminidase-deficient influenza virus infection did not reduce mortality after secondary lung bacterial infection in mice [20].2. Reduced airway clearance Influenza virus impairs airway epithelial cilia function, resulting in reduced mechanical clearance of bacteria by the airway epithelium [21, 22], as Disruption of alveolar surface active substances leading to small airway occlusion, increased mucus and fibrin secretion, and inflammatory cell infiltration leading to increased secretion of inflammatory factors, providing an environment for bacteria to stay and grow [23, 24]. Chronic airway diseases, such as chronic obstructive pulmonary disease (COPD) and bronchiectasis, resulting in airway obstruction and inflammation are also exacerbated by influenza virus infection, creating conditions for bacterial growth [25, 26].3. Leukopenia and impaired function following influenza virus infection are closely associated with secondary bacterial infection [6, 27]. Secretion of type I IFN in the lungs of mice after influenza virus infection inhibits IL-17 production by γδ T lymphocytes, which in turn inhibits neutrophil recruitment [28, 29]. Influenza virus promotes apoptosis of alveolar macrophages and inhibits their phagocytosis [30-33], and this effect is most pronounced 7-8 days after infection, when effector T cells enter the airway and IFN-γ secretion is at its peak [33]. iFN-γ inhibits macrophage phagocytosis of Staphylococcus aureus [34] and inhibits macrophage expression of the scavenger receptor MARCO and bacterial clearance, whereas influenza virus expressing IFN-γ in the lungs of mice infected with influenza virus, the expression of TNF-α was significantly reduced [33]. Influenza virus inhibits TLR4 receptor signaling on the surface of alveolar macrophages and can persist for months [32]. Influenza virus also significantly increases the expression of CD200 receptors on the surface of alveolar macrophages and inhibits the activation of alveolar macrophages secondary to bacterial infection [35].4. Airway inflammatory imbalance Influenza virus infection initiates the secretion of various cytokines, such as pro-inflammatory factors like type I IFN-γ, IL-1 and IL-6 to promote clearance of influenza virus, and anti-inflammatory factors like IL-10 and TGF-β avoid excessive inflammatory responses [36-38]. The overexpression of these inflammatory factors leads to an imbalance of inflammation in the lung and promotes bacterial and viral growth [39]. Both Spanish influenza and H5N1 avian influenza infections have been shown to cause excessive inflammatory responses in the lung [40-42]. PB1-F2 (a novel pre-apoptotic protein) produced after viral infection mediates excessive inflammation and secondary bacterial infection of the lung [43-45]. Influenza virus-induced type I IFN-γ significantly inhibits the secretion of IL-17, IL-22 and IL-23 by the TH17 cell subpopulation, which in turn inhibits clearance of Streptococcus pneumoniae and Staphylococcus aureus from the lung [46]. Increased secretion of the anti-inflammatory factor IL-10 also increases the susceptibility of the organism to Streptococcus pneumoniae [47]. Third, the choice of antimicrobial drugs is not required in viral infections, which is well known, but in reality about 75% of Chinese outpatients with colds apply antimicrobial drugs. And overtime, overdose, untargeted or not strictly regulated use of antimicrobial drugs are all abused antimicrobial drugs. Misuse of antimicrobial drugs in viral infections is very likely to lead to bacterial resistance, and once the real infection later antimicrobial drugs are instead insensitive, leading to treatment failure while increasing unnecessary medical expenses.1. Determination of secondary bacterial infections after respiratory viral infections Secondary bacterial infections have so far no diagnostic and treatment criteria. Confirmed cases of influenza without evidence of bacterial infection or where mixed bacterial infection can be excluded are not indicated for the use of antimicrobial drugs, and prophylactic application of antimicrobial drugs is not recommended [48]. Influenza viruses reach their peak replication 3-5 days after infection of the body and are completely cleared by the body after 10-12 days. Increased susceptibility to bacteria in patients with influenza begins after the peak of influenza virus replication and lasts for 2 weeks or even months. Thus, secondary bacterial infections usually occur about 7-10 days after influenza virus infection [1]. Patients with influenza simplex who present with obvious signs of bacterial infection after improvement of fever and systemic toxicity, such as cough, purulent sputum, or renewed fever, new pulmonary infiltrate or solid shadow on chest imaging, and elevated blood leukocyte and neutrophil ratios, need to be considered for possible secondary pulmonary bacterial infection and treated with antibacterial drugs. The elderly, children and the frail, and those with pre-existing underlying diseases, whose body resistance is poor, are susceptible to co-infection with bacteria and can be very ill once co-infected and should be treated with antibacterial drugs early when there is a hint of bacterial infection. It is important to note that patients with pneumonic influenza are also commonly seen in the elderly, children, or patients with other co-morbidities, but their sputum smear is usually devoid of bacteria; therefore, when these patients have obvious respiratory symptoms such as coughing and sputum production, scattered infiltrative shadows in both lungs are seen on chest imaging, and bacteria engulfed by neutrophils are found on sputum smear, secondary bacterial pneumonia should be considered. Sputum smear and peripheral blood calcitoninogen (PCT) testing can promptly help determine whether there is a secondary bacterial infection, and culture of lower respiratory secretions can provide assistance for targeted antimicrobial therapy [8, 49].2. The common pathogens of secondary bacterial infections in influenza are Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae [1, 6, 8, 50-52]. Among them, Streptococcus pneumoniae infection has the highest incidence [1], followed by Staphylococcus aureus. S. aureus was the most common co-infecting bacterium during the 1957 Asian influenza pandemic, the 1968 Hong Kong influenza pandemic, and the 2009 H1N1 influenza pandemic, and the isolation rate of methicillin-resistant Staphylococcus Aureus (MRSA) was higher than that of methicillin Methicillin Susceptible Staphylococcus Aureus (MSSA) [6, 8, 49, 51, 53, 54]; Streptococcus pseudomallei infection rate is the third [55], and Haemophilus influenzae infection is mostly seen in pediatric influenza patients. Bacterial co-infections or secondary infections can vary by influenza epidemic season, viral strain, epidemic location, and population. The gradual spread of streptococcal vaccination may also change the type of secondary bacterial infection. The pathogen distribution of secondary bacterial infections is similar to that of late onset Hospital Acquired Pneumonia (HAP) if the hospital stay is prolonged, especially in patients admitted to the ICU.3. Antimicrobial drug selection for secondary bacterial infections Targeted antimicrobial therapy requires a combination of seasonal, local and population-specific evidence of influenza epidemics. microbiological evidence. Because available epidemiologic investigations confirm that the most common secondary infecting bacteria are Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes. The choice of antimicrobial agents for empiric therapy may follow the guidelines for the diagnosis and treatment of CAP, choosing either a second-generation cephalosporin, or a beta-lactam/beta-lactamase inhibitor combination alone or in combination with a macrolide, or a respiratory quinolone. Most patients with severe influenza, even those requiring mechanically assisted ventilation, and especially those with severe influenza combined with other underlying diseases, require hospitalization, so empirical antimicrobial drug selection for secondary bacterial infections needs to follow the diagnostic and therapeutic guidelines for HAP [56], and depending on the risk of multi-drug resistant bacterial infections, choose a third-generation cephalosporin against gram-negative bacteria, or a respiratory quinolone, or a respiratory quinolone with anti-pseudomonas functional cephalosporins, carbapenems. In view of the current high isolation rate of MRSA, if chest imaging does not exclude the possibility of combined Staphylococcus aureus infection, a combination of glycopeptides (vancomycin or teicoplanin) or linezolid therapy is required. The mechanisms of secondary and combined bacterial infections in influenza need to be further explored, and the epidemiological data also need to be urgently studied in large-scale clinical studies, especially the diagnostic and treatment criteria need to be summarized in a large number of clinical studies, and there is still a long way ahead. Li Pei Shi Yi