Influenza and the Surgeon

Abstract

Background:

The influenza virus is a pathogenic virus responsible for large numbers of deaths and long-term disabilities worldwide. Although the very young, the very old, and immunocompromised individuals are most susceptible, the effects of the influenza virus can be observed across the entire spectrum of individuals.

Discussion:

Infection with the influenza virus induces a substantial inflammatory and immunologic response and induces marked pulmonary inflammation. Many aspects of influenza affect surgical patients directly. Vaccines are one of the most effective measures aimed at reducing the prevalence and severity of many infectious diseases, including the influenza virus. Vaccination programs remain one of the highest priorities across the spectrum of countries, research institutions such as the National Institutes of Health, international health agencies such as the World Health Organization (WHO), and major non-profit organizations.

Conclusion:

This review addresses aspects of the immune and inflammatory response to influenza, with a focus on the elderly population and healthcare providers who may act as reservoirs for virus transmission to the vulnerable surgical population.

The specter of the 1918 Spanish influenza pandemic still casts a long shadow over many aspects of influenza policies and patient care [1]. This pandemic, one of the deadliest public health crises in human history, led to more than 50 million deaths worldwide [2]. A concerning finding common to the influenza pandemics over the ensuing century, including the most recent outbreak, has been the involvement of young and otherwise healthy individuals and not just elderly and medically frail patients [3,4]. The most recent pandemic occurring in 2009 involved the H1N1 subtype with much of the worldwide spread being attributed to the ease of national and international travel [5]. It is estimated that 10% of adults are affected by influenza infections annually [6]. The influenza virus is still responsible for large numbers of deaths as well as secondary respiratory and cardiac complications. There are approximately eight hospitalizations for every one flu-related death. Both seasonal and pandemic occurrences of influenza outbreaks pose huge economic burdens through cost of providing care as well as lost days of productivity.

The Influenza Virus

The influenza virus is a segmented negative-sense RNA virus, consisting of eight segments of single-stranded RNA. The eight gene segments encode for 13 known proteins that are capable of rapid mutation [7]. There are two main subtypes of influenza virus that are known to affect humans, type A and type B. Humans are the almost exclusive host for the influenza B virus, whereas a variety of hosts exist for influenza A. Influenza type A is the predominant pathogen involved in severe seasonal pandemics and epidemics. A third variety, influenza virus type C, is only associated with very mild symptoms [8]. The influenza viruses are part of the Orthomyxoviridae family. Virus replication involves an RNA-dependent RNA polymerase that is noted to lack proofreading capability. This error-prone form of viral RNA polymerase can lead to alterations occurring during replication that may produce a substantial degree of viral diversity, known as variants [9]. Whereas these variants contribute to the ability of the virus to survive diverse environmental conditions, they also make immunologic memory, appropriate immune response, and vaccine development difficult every year.

The segmented nature of the genome allows gene exchange between different influenza strains within the same cell. Indeed, variants from the 1918 pandemic are believed to have been present in the recent 2009 outbreak. Interactions between subtypes are also believed to have been responsible for the pandemics in the 1950s and 1960s [10]. Antigenic shift, caused by gene exchange, leads to rapid changes in the antigenicity of the virus, whereas mutations (antigenic drift) lead to more gradual changes in the virus. Influenza A virus demonstrates high rates of genetic diversity. Influenza B demonstrates lower rates of antigenic drift. Because of the high rate of virus variants, there are often many different influenza populations within any one seasonal outbreak [11]. Viral strain interactions can occur in either a competitive pattern between virus clones or can occur via virus clone cooperation to make viral functions or dissemination easier [12]. These viral clone cooperative interactions often make an infection with influenza more pathogenic as well as leading to a more pronounced immune and inflammatory response.

The high mutation rate of the influenza virus means that the influenza virus cannot be managed with a single lifelong vaccine, but rather current influenza vaccines need to be re-formulated annually to best match the circulating seasonal strains. Vaccine development for any one particular season attempts to target as many different identified strains for that year. However, elimination or minimizing the dominant strain for a particular year may allow for the emergence of minor variants of the virus, potentially leading to second or third waves of outbreaks per year [11]. Strong pathogenic second and third waves of influenza infection among communities has often been a hallmark of the pandemics and have been associated with considerable numbers of influenza-related deaths.

Diagnosis of Influenza Infection

Early symptoms of a potential infection with influenza virus may include the presence of cough or fever. However, outside of a known influenza outbreak within a community, there are no clinical features that are specific enough to be able to distinguish the early phase of influenza infection from other milder respiratory viral infections accurately. The classic symptomatology of the typical seasonal influenza infection includes ongoing fevers, headaches, myalgias, muscle weakness, cough, and upper respiratory tract symptoms. In this context, given the effects of aging on inflammation and immune responses [13,14], one must be cognizant that elderly patients are less likely to display classic influenza symptoms. Confusion in an elderly person is often indicative of an infectious process.

Self-diagnosis or self-surveillance is a key factor in controlling potential spread of influenza infection. However, self-diagnosis does not correlate accurately with seropositivity for influenza. Rates of influenza virus-positive culture appear to be no different between individuals who report symptoms versus those who claim no symptoms. Jutel et al. [15] noted that 23% of individuals reporting influenza-like symptoms were seropositive during the 2009 influenza H1N1 outbreak, which equaled rates of seropositivity (21%) among patients who reported no symptoms of influenza infection. False-positive clinical suspicion, or overdiagnosis, based on mild symptomology could lead to excessively large numbers of staff being told not to report to work. However, under-recognition of a potential infection increases the risk of viral transmission. Shedding of influenza viral particles is noted to begin 24 hours prior to symptoms. The typical duration of infection may last up four to five days. Viral shedding is noted to continue to occur up to five days after resolution of symptoms [16]. Given the need for providers of surgical care to be in close proximity to surgical patients, transmission can occur easily during this extended period of time. In addition to clinical features, specific tests may be useful in diagnosing individuals with influenza. A detailed discussion regarding testing recommendations is beyond the scope of this review, but is available in a recent position paper that outlines specific recommendations for testing for seasonal influenza [17]. Samples collected from the throat or nasopharyngeal mucosa can be tested for the presence of viral antigens. However, detection of viral antigens has a high false-negative rate and should not be used exclusively to rule out infection. Although advanced testing modalities are more accurate, they are also more expensive. Polymerase chain reaction (PCR) is specific for virus detection, but is often not present in smaller institutions, and may lack the ability to detect variants of the virus. Culture of virus is discourage given the major time limitation for the culture to be performed.

Inflammation and Influenza

Respiratory tract infection with influenza virus induces a rapid and profound immune response. Epithelial cells, vital to alveolar integrity, are targeted early during an influenza infection [18], with marked damage to the integrity of tight junctions. Infection is associated with an induction of a significant inflammasome [19]. Inflammatory cytokines are derived from both the pulmonary epithelium as well as from the influxing monocytes and neutrophils and the resident alveolar macrophages. The degree of cytokine production, such as interleukin (IL)-6, in response to the influenza virus correlates directly with the degree of pulmonary damage [20]. Alveolar macrophages play key central roles in viral clearance in part through production of interferon (IFN)-β [21], and a substantial depletion of alveolar macrophage, often via virus-induced macrophage apoptosis, is associated with marked risk of mortality during an infection [20,22]. Neutrophils have been shown to influx approximately two days after infection wherein they play a central role in disease resolution and virus clearance. However, neutrophil influx has conflicting effects during viral infection. Although neutrophils are essential to viral clearance, these activated neutrophils also induce substantial collateral epithelial inflammation, damage, and edema. The chemokines and cytokines produced during an influenza infection are also capable of inducing further cycles of influxing neutrophils and macrophages. This positive feedforward cytokine cycling of proinflammatory mediators is often driven by poorly controlled virus infection or by re-infection when a patient re-contacts a virally infected community [23]. Activated leukocytes and infected alveolar epithelium further lead to nitric oxide and reactive oxygen species production that can further damage the epithelial barrier [24]. Furthermore, influenza virus infection can induce epithelial cell layer apoptosis and necrosis. This damage subsequently manifests as the well-recognized clinical and radiographic findings. The severity of influenza-induced epithelial damage is reflected in the degree of lung edema, impaired gas exchange, and ultimately respiratory failure.

Secondary Infections

Secondary bacterial pulmonary infections are the most recognized secondary critical consequences of infection with the influenza virus. Development of bacterial pneumonia adds substantial morbidity and mortality to an influenza infection [3]. Those most susceptible to the development of a secondary bacterial infection include children, the elderly, individuals with poor nutrition, patients with multiple medical comorbidities including mental health issues, and individuals who are immunocompromised. Secondary bacterial coinfections among otherwise healthy individuals are most pronounced during pandemics [25]. It is critical to remember that surgical patients display a relative immunosuppressive state in the post-operative phase. Surgical stress is known to produce substantial alterations in both innate and adaptive immune systems, including macrophages, dendritic cells (DCs), and lymphocyte populations, including the innate regulatory lymphocyte subset of γδ T-cells [26,27].

Macrophages play important roles in maintenance of the airways in healthy individuals. There are three airway macrophage populations, each playing distinct roles in health, pathogen elimination, and inflammation resolution [26,28]. In a healthy state, alveolar macrophages are rather tolerant to cellular debris and otherwise innocuous antigens. Alveolar macrophages have a high threshold for activation, lowered phagocytic activity, and lowered respiratory burst. In comparison, interstitial macrophages play a major role in tissue re-modeling and controlling tissue fibrosis and display a greater ability to present antigen. Macrophages in conjunction with DCs act to inhibit T-cell activation in the airway, which may induce tolerance to otherwise innocuous airway antigens. Furthermore, the airway epithelium, through factors including IL-10 and transforming growth factor (TGF)-β, is capable of regulating and inducing alveolar macrophage hypo-responsiveness preventing inappropriate macrophage activity. Conversely, this negative regulation of macrophages may also lead to a delayed immune response to viral infection. Although reduced IL-10 concentrations may lead to enhanced early viral clearance, it also leads to excessive macrophage activity with ensuing epithelial injury, loss of barrier integrity, and an environment ripe for secondary bacterial infection [29]. Airway macrophages are depleted rapidly during an influenza virus infection. The re-populated macrophages may be derived from either bone marrow-derived monocytes or from the remaining lung interstitial macrophage population. These new macrophages induce further inflammation and tissue injury as they act to clear the pulmonary environment of injurious material attempting to return the lung to a state of health. This cycle can lead to damage of the underlying epithelium allowing bacterial colonization to develop into a bacterial infection.

Dendritic cells are located in the interstitial spaces and along the pulmonary epithelium. Dendritic cells play a role in surveilling the micro-environment and in clearing injured and apoptotic cells [30]. During inflammation or infection DCs transport apoptotic cells to draining lymph nodes and are capable of presenting apoptotic cell antigen to CD8⁺ T-cells. Although γδ T-cells in general are a minor subpopulation of lymphocytes, they account for up to 10% of lung lymphocytes [31]. Gamma/delta T-cells are a subpopulation of innate regulatory lymphocytes with prominent roles along mucosal surfaces. They regulate a large spectrum of the immune response. Gamma/delta T-cells are capable of recognizing and responding to a variety of pathogen-associated molecular patterns (PAMPs) and, with respect to infection profile, they are capable of producing several antimicrobial peptides. Interleukin-17, produced by γδ T-cells, plays an important function in bacterial clearance during infection. Notably, IL-17 production by γδ T-cells is reduced substantially during influenza infection, which leads to an increased risk for Streptococcus pneumoniae infection [32]. With respect to surgical stress, both circulating and pulmonary γδ T-cells have been shown to be markedly affected after operative interventions, traumatic injuries, and surgical septic events [27,33,34].

Among the spectrum of cytokines involved in the post-viral repair response, IL-10 is a particularly important link for surgical patients. The immune response to a viral infection leads to substantial pulmonary epithelial injury. The post-viral immune and inflammatory response switches, in part, toward a tissue repair profile and away from microbe clearance and induces an elevation of IL-10. The post-influenza immunomodulatory effects of IL-10 consist of dampening cellular aspects of microbe clearance and favor immune-mediated tissue repair and re-modeling. This relative immunosuppression induced by IL-10 promotes bacterial growth [35], leading to a subsequent increased risk for secondary bacterial pneumonia. Importantly, surgical procedures, both small and large, are also associated with elevated systemic IL-10 as part of the wound healing process. Kokotovic et al. [36] noted in a large review that even a minor procedure such as an inguinal hernia repair induced marked elevation of systemic IL-10 concentrations post-operatively. Alterations in IL-10 by either process, influenza infection or surgical stress, induces its immunosuppressive function through alteration of multiple aspects of the immune system, including T-cell–mediated immunity. Specifically, during wound repair, as observed in surgical patients or post-viral infection, IL-10 affects regulatory T-cells and helper T cell (T_H) 17-producing lymphocytes. These cells are critical to both wound healing and microbe clearance. The interaction between IL-10 and T_H17 cells is critical to both superficial wound healing as well as intestinal epithelial inflammation [37], and the immunosuppressive effect of IL-10 potentially increases the risk of post-operative complications including increased risk of infection. Morgan et al. [26] described the benefits of a rapid IL-10 inflammatory response to influenza, arguing that a short burst of inflammation may be associated with rapid viral clearance and less pulmonary tissue injury, thereby lowering the risk for secondary bacterial infections. Although in principle this may be effective, it has been shown that older surgical patients do not display the standard rapid increase in inflammatory markers, but rather a dampened and more prolonged inflammatory response. Indeed when geriatric patients do exhibit the fast burst of inflammation their mortality is markedly increased [13]. Surgeons need to exercise caution when considering elective operative interventions in patients in the post-influenza infection recovery phase.

When a secondary bacterial infection is suspected, culture data is very useful in directing appropriate antimicrobial therapy. Bacteria that are often involved include Hemophilus influenza, Streptococcus pneumoniae, and Staphylococcus aureus. Although the viral organisms involved in the 1957–1958 pandemic are believed to have had lower pathogenicity compared with other pandemic outbreaks, the majority of influenza-related deaths during that outbreak were attributed to secondary bacterial pneumonia. Whereas an infrequent cause of deaths in other pandemics, Staphylococcus aureus was the leading bacterial isolate from the 1957 pandemic [38]. Hemophilus influenza as a secondary bacterial cause of influenza-related deaths has been on the decline in the recent past, potentially because of the combination of childhood vaccinations as well as evolving antibiotic usage patterns [25]. It has been observed that infection with influenza virus interacts with otherwise non-pathogenic bacteria leading to greater virulence of disease, increased rates of death, and, among those who died, shortened time to death [39]. Conversely, it has been demonstrated that the influenza vaccine may prevent bacterial coinfection or severity of bacterial coinfection [40,41]. Less common bacteria such as Legionella pneumophila have increased in frequency over the past several decades [42]. Given the increasing rate of antimicrobial resistance, a major fear for future pandemics is the potential for large numbers of patients to be secondarily infected with resistant bacteria such as methicillin-resistant Staphylococcus aureus or with highly pathogenic clones of Streptococcus pyogenes [5,43,44].

Cardiovascular Effects of Influenza

Cardiovascular complications are relatively common after non-cardiac surgery, especially among older patients. Our understanding of the etiology, incidence, and impact of cardiac events has broadened substantially over the past two decades. Even an asymptomatic troponin rise after a non-cardiac operation carries a substantial increase in peri-operative risk for morbidity and mortality [45,46]. Interventions such as β-blocker or statin therapy have reduced the risk of cardiovascular events in high-risk patients. Infection with the influenza virus may lead to vascular thrombosis. The myocardium is noted to be specifically vulnerable to the inflammatory effects of influenza virus. In a study involving patients aged 65 years and older, Smeeth et al. [47] noted a dramatic increase in the risk of stroke or myocardial infarction in the immediate period after diagnosis of an influenza infection. Most concerning to a surgical population, it was noted within this study that the risk of a cardiovascular event persisted for up to three months, with a five-fold increased risk of developing a myocardial infarction within the 90 days after infection with the influenza virus [47]. These events have been linked to substantial alterations in systemic inflammatory mediators. Vascular-related deaths among elderly patients have been demonstrated to have a seasonal variation with peak incidence during the influenza season. Cardiovascular-related deaths also vary between years with a pattern tracking the severity of influenza outbreaks for those years. Although death from respiratory causes increases during influenza epidemics, the greatest absolute increase in mortality rates were often caused by cardiovascular diseases and deaths from ischemic heart disease [48].

Inflammation, including peri-operative inflammation, poses a substantial risk for the development of dysrhythmias including atrial fibrillation. This includes both infiltration of activated immune cells as well as inflammatory cytokines. Cardiac electrophysiology and calcium homeostasis can be altered by these mediators of inflammation thereby leading to dysrhythmias such as atrial fibrillation [49]. Chang et al. [50] demonstrated that influenza infection was associated with an 18% increased risk for developing atrial fibrillation. This risk was reduced to baseline among patients who received the influenza vaccine. In a series of prospective population-based studies of patients with atrial fibrillation, it was demonstrated that the risk of atrial fibrillation-related ischemic stroke [51] and hemorrhagic stroke [52] was substantially lower in patients who received the influenza vaccine compared with individuals who did not undergo vaccination.

Influenza Vaccination

The U.S. Office of Disease Prevention and Health Promotion's Healthy People 2020 set a target of 70% influenza vaccination coverage. Vaccination programs remain one of the highest priorities across the spectrum of countries, research institutions such as the National Institutes of Health (NIH), international health agencies such as the World Health Organization (WHO), and major non-profit organizations such as the Gates Foundation [53]. The effectiveness of vaccines worldwide has been reflected by numerous studies [8,53 –55]. In a review of more than 14,000 hospitalized surgical patients, Tartof et al. [56] demonstrated that an in-hospital influenza vaccination program was safe and effective. Vaccination is a well-proven cost-effective approach to reducing the incidence of influenza infection, lessening the severity of infection and reducing influenza-related complications among both small and large population studies [57]. Despite many campaigns and much advocacy, the actual vaccination rate remains dismally below this target ranging between 30% and 60%. The biggest challenge in vaccination against influenza virus is the constantly changing antigenicity of the virus year after year. Unlike many other vaccines that can last from many years to potentially lifetime immunity, the constantly changing nature of the influenza virus from year to year mandates individuals receive annual vaccination. This fact is often either under-perceived or frankly dismissed by many individuals including those in the healthcare industry.

Seasonal specific vaccine development commences seven to eight months in advance of influenza season with evaluation of circulating strains and assessment of antigenic drift. This occurs twice yearly, one each for northern and southern hemispheres. Seasonal influenza vaccines constitute either inactivated, live attenuated, or recombinant hemagglutinin (HA) vaccines, however, recent recommendations have veered away from the live attenuated vaccine in light of the low effectiveness against the influenza A(H1N1)pdm09 [58]. Among the inactivated vaccine, a higher dose vaccine is available and recommended for elderly patients aged 65 years and older in order to increase the immunogenicity of the vaccine. Vaccination with the live attenuated is usually reserved for healthy younger adults under 50 years of age, and is noted to be effective against antigenically drifted influenza strains [59]. The recombinant HA vaccine is also recommended for adults under age 50 and can be administered to individuals with an allergy to eggs. A significant focus of influenza vaccine development is to target the HA protein because it mediates viral entry. Because of the shorter time required for manufacturing of this vaccine it has been especially useful in pandemic responses. Vaccine-related adverse events are uncommon and mild in nature. The most common effects are injection site pain or mild upper respiratory tract symptoms. Current recommendations are for annual vaccination to be administered to individuals aged six months and older, with special attention to geriatric individuals, immunocompromised patients or those with chronic medical comorbidities, and healthcare providers [17,58].

Identification of the global circulating influenza strains is a critical step in vaccine development. However, when second-wave strains appear in circulation that were not identified months previously, the time to develop a newer vaccine can be prohibitive. This occurred with the 2009 H1N1pdm strain that was prevalent in the second wave of the 2009 pandemic [60]. Annual revaccination is required because of a combination of antigenic drift among circulating virus strains as well as a natural decline in vaccine-specific antibodies. Vaccine developmental research continues to try to identify means to prolong the effectiveness of the influenza vaccine. One intriguing prospect is to target the conserved portion of the HA stem [61]. The HA stem is conserved across wide variations of the influenza virus. Hemagglutinin stem antibodies are capable of recognizing multiple subtypes within the same originating group. With the ongoing developments and vaccine research, administration of the annual influenza vaccine has been shown to be relatively effective even when the vaccine match to circulating strain is poor.

The Aging Surgical Population

Both the global and U.S. populations are aging rapidly. It is estimated that there are currently more than 650 million individuals aged over 65 years worldwide [62]. Elderly patients constitute increasingly large quantities of both elective and emergent surgical populations. It is therefore imperative for surgeons and surgical staff to understand the impact of influenza upon this vulnerable population. The aging of the world's population poses unique stresses upon global healthcare systems, with infections constituting leading causes of death and long-term morbidity for elderly patients. Specifically, with respect to seasonal influenza infection, it is elderly patients who suffer the highest rates of both direct and secondary influenza-related complications including death. According to the U.S. Centers for Disease Control and Prevention (CDC) 2017–2018 report, patients aged 65 years and old accounted for the single largest group of patients affected by the influenza virus [63]. The elderly population account for the majority of influenza hospitalizations including both excess admissions as well as accounting for number of excess hospital bed utilization [64]. This geriatric group displayed a greater severity of influenza-related illness, accounted for 59% of influenza-associated hospitalizations and had the highest influenza-related mortality rate. Most concerning is the fact that among patients aged 50 years and older, one influenza related death occurs for every eight hospitalizations [65].

Elderly patients have many contributing factors that adversely affect the impact of an episode of influenza. The risk of developing post-influenza pneumonia has been shown to correlate directly with the number of concurrent medical comorbidities. Elderly patients have considerable difficulty in either clearing a virus infection or dealing with the pulmonary effect of a viral infection. An age-related decline in pulmonary physiology also contributes to the respiratory consequences of a respiratory viral infection with a lowered effective pulmonary toileting. Elderly patients exhibit a lowered physiologic reserve, muscle decline with less efficient and less forceful cough, and a less efficient mucociliary escalator mechanism [66]. A surgical incision, especially if pain control is inadequate, greatly impacts the respiratory effort and the fragile physiology of an elderly patient.

The Geriatric Immune System and Vaccines

Across a spectrum of diseases, it has been well documented that prevention programs, rather than reactive treatment programs, are far superior to health quality among elderly patients. This is especially true for predictable events such as seasonable influenza occurrence as well as pandemic influenza infections. The influenza vaccine has consistently been proven to be effective in limiting disease occurrence and disease severity among geriatric patients [57,67,68]. However, not all elderly patients are the same. There is a large diversity of physical, mental, and immunologic health among the single cohort of the elderly population. Chronologic aging often mirrors immunologic aging or immunosenescence, which leads to different risks for developing influenza, suffering consequences of influenza, and also the immune response to both the virus and any vaccine [67]. We echo the statement of Aspinall et al. [62] that it may be inappropriate to ascribe a single biology, and thus vaccination policy, to such a large and diverse population based upon a single chronologic feature. The effectiveness of the influenza vaccine can vary considerably among elderly individuals for a variety of reasons. Surgical providers need to be aware of the challenges posed by this diversity when offering or timing operative interventions. There are now several knowns mechanisms of poor immune response after influenza infection and reasons for relative ineffectiveness of the influenza vaccine among elderly patients.

Immunosenescence is also related to repeated exposures to antigens as well as repeated clinical and subclinical infections and is associated with an underlying state of chronic inflammation. Clinical markers of frailty often correlate well with the degree of immunosenescence [67,69 –72]. Age-related changes in the first line and innate immune responses to influenza decrease the initial attempts at viral elimination. This is driven, in part, by altered toll-like receptor (TLR) responses and inappropriate compensatory cytokine production. Aberrant cytokine response from aged DCs after stimulation with TLR ligands is associated with diminished influenza virus clearance. Furthermore, altered TLR response led to dampened vaccine-induced antibody production [70]. The other important component of the aging immune system involves pronounced involution of the thymus, which leads to decreased number and effectiveness of circulating new naïve T-cells [72]. A robust diversity of T-cell receptors (TCRs) is critical to a full immune response to influenza infection. Older individuals are noted to have a markedly lowered range of TCR diversity. This diminished T-cell diversity leads to a persistence of a variety of viral infections including the influenza virus [69]. Costimulatory proteins are key to the diversity of T-cell responses. The costimulatory molecule CD28 is required for naïve T-cell differentiation after an antigen exposure and is noted to decline with chronologic aging. This decline in CD28 expression upon CD8⁺-T-cells is also directly related to a diminished immune response to an influenza vaccine. Goronzy et al. [71] noted that a 10% decline in CD28⁺-CD8⁺ T-cells was associated with a 25% decrease in the immune response to the influenza vaccine. Furthermore, the primary B-cell response in an elderly individual is often dampened and short-lived resulting in antibodies with relatively low affinity. The checkpoint protein B and T Lymphocyte Attenuator (BTLA) is a key modulator of lymphocyte function in both short- and long-term immune responses to infections. A decline in BTLA expression upon B-cells with aging leads to an inability of B-cells to contribute a sustained antibody response. B-cell responses to both infection and vaccine are partly dependent upon additional contributions from helper T-cells [67]. Aging induces a decline in function of CD4⁺ T-cells and reduced expression of T-cell costimulatory receptors such as CD40 that cofunction with B-cells [72].

Beyond an aging immune system, there are also surgically relevant medications that are known to interact with the vaccine or to contribute to reduced vaccine efficiency [14]. Elderly patients, with coexistent medical conditions, are often prescribed a multitude of medications [73]. Rates of polypharmacy range from 25% of noninstitutionalized patients [74] to more than 60% of institutionalized patients [75]. Several surgically important influenza vaccine-drug interactions are now recognized. Anticoagulation therapy including warfarin is often used therapeutically in vascular surgery patients or prophylactically among orthopedic patients undergoing total joint replacement. The interaction between influenza vaccine and warfarin is believed to involve a non-specific mechanism between the vaccine and the hepatic cytochrome P-450 system [76]. Statins are often used as cardiovascular protective agents in surgical patients. Statins have been demonstrated to have multiple effects with respect to the influenza virus and vaccine. Immunologically, individuals receiving long-term statin therapy were noted to display reduced influenza virus neutralizing antibody titers [77]. Furthermore McLean et al. [78] demonstrated that vaccine effectiveness against the H1N1 virus was reduced among patients taking statin therapy. Long-term statin use induces alterations in the programmed cell death receptor (PD-1/PD-L1) pathway upon B-cells [14) leading to dampened B-cell responses. The use of over-the-counter analgesics including non-steroidal anti-inflammatory drugs (NSAIDs) has increased rapidly among elderly individuals over the past decade. Although NSAIDs are excellent non-narcotic post-operative analgesics for elderly patients, long-term NSAID use has been associated with altered immune function. As noted above, γδ T-cells are innate regulatory lymphocytes that play essential immune regulatory roles, including coordinating pathogen elimination at the pulmonary mucosal level. Furthermore, γδ T-cells are crucial for full vaccine-mediated immunity. Long-term NSAID use was associated with substantially reduced baseline circulating γδ T-cell populations. Furthermore, patients on long-term NSAID therapy also displayed diminished B-cell reactivity and altered PD-L2 expression upon B-cells [14].

Influenza and Healthcare Workers

Drago et al. [79] estimated that approximately eight million U.S. workers attend work annually while infected with influenza virus. The authors noted that these infected workers were estimated to transmit their influenza infection to an additional seven million coworkers. This workplace transmission has been noted to contribute to substantial additional lost workdays [79]. During the 2009 pandemic the average prevalence of infection among healthcare providers was reported as 6.3% [80], with some reports noting a prevalence as high as 40% of healthcare providers [81,82]. Overall, compared with non-healthcare providers, individuals whose work involved patient contact were noted to have a two-fold increased risk of being infected with the H1N1 virus during the 2009 pandemic [80]. In a study in 2009, prior to peak occurrence of influenza pandemic in Spain, Olalla et al. [83] demonstrated that more than 25% of all healthcare workers had positive serology for the influenza A (H1N1) 2009 virus, many of whom denied symptoms. Importantly the highest rate was noted among the individuals whose primary job involved patient transport, with 42% demonstrating positive serology. This included many individuals who would be instrumental in transporting or transferring surgical patients to, from, or within the operating suites. Expectedly the hospital area with the highest prevalence was the emergency department, however the rates among individuals in the surgical arena was also disturbingly high. Presenteeism, or working while sick, is a substantial source of transmission of virus from healthcare provider to surgical patients. Chiu et al. [84] reported that 41% of healthcare providers continued to work despite being sick. The highest presenteeism rate was among hospital-based workers. Rates were highest among physicians (63.2%) and pharmacists (67.2%). The two most common reasons for continuing to work while sick were feeling well enough to work and a stated inability to afford the loss of pay.

The risk of transmitting occupationally acquired influenza to patients is highest among non-vaccinated healthcare providers [80]. Despite understanding this risk as well understanding the critical role for healthcare providers in preventing transmission/infection, voluntary compliance with annual influenza vaccination is surprisingly low. In a review of healthcare providers' attitudes toward compliance with vaccination, Ciftci et al. [85] noted that vaccination rates rose with increasing age, were substantially higher among female providers (32% vs. 21.5%), were highest among physicians (41.2%) and healthcare assistants (28.3%) and were lowest among medical administrative staff (21.3%). Within each job category, vaccination rates were highest among individuals who had been in the same job post for at least five years (62.6%). Sadly, a self-reported lack of understanding of the nature or consequences of influenza infection was among the most common reasons cited by healthcare providers for not receiving an annual influenza vaccine. There are approximately four million individuals residing in nursing homes and other long-term facilities in the United States, with a substantial portion of these patients recovering from major operative interventions. Vaccination of not just the residents, but also vaccination of the staff of such facilities has been shown to decrease both the incidence and the severity of influenza among nursing home and long-term facility patients [86].

Transmission and Asymptomatic Spread

It is well accepted that transmission rates are reported to be highest among patients who are most symptomatic. However, it is also increasingly recognized that transmission of the virus from an asymptomatic individual is possible, thereby contributing to a silent and underappreciated risk of virus spread [87,88]. Asymptomatic infection is defined as an infection occurring within an individual who does not display any signs or symptoms of an infection. This is also termed the asymptomatic fraction of a seasonal outbreak or pandemic occurrence and defines the individuals who test positive for virus and display other serologic markers of the infection. There is wide variability among studies as to what percentage of individuals constitute this asymptomatic fraction. Much of the controversy also surrounds the definition of asymptomatic infection versus carrier. The best estimates range from 14% to 24% of individuals within any sampled population would be considered defined as asymptomatic infection.

The proportion of transmission by these asymptomatic individuals is known as the theta factor [89]. The rate of transmission from an asymptomatic but infected individual is reported to be approximately one-third the rate of transmission from symptomatic individuals [90,91]. Thus, in seasons of high transmission rates among symptomatic patients, the noted transmission rates among asymptomatic patients is also noted to be relatively high. Fraser et al. [91] used contact tracing and computational modeling to determine the proportion of asymptomatic individuals during a seasonal influenza outbreak. This, along with several other studies, have now shown that the theta factor can be decreased with increasing vaccination uptake among the larger general community. Importantly, they identified that increasing vaccine compliance among the population as a whole and isolating asymptomatically infected individuals were two critical factors that can contribute to reducing the severity of an influenza outbreak among a community.

Influenza is predominantly transmitted via aerosolized droplets. It is a long-held misconception that a forceful expulsion of viral particles, such as that caused by a sneeze or cough, is essential to spread viral particles from person to person. However, it is now well documented that spread of influenza virus particles may occur through both passive actions such speaking to patients as well as forceful actions. Yan et al. [92] demonstrated that even with non-forceful speaking, viral particles can be shed up to six feet away from an either overtly symptomatic patients as well as from asymptomatically infected individuals. Although cough was a strong predictor of incidence and quantity of viral shedding, the authors detected virus in 48% of samples obtained from individuals who did not cough or sneeze but were merely speaking during sample collection. Among individuals who are asymptomatically infected, viral shedding can last between three and seven days. The distance needed for virus particle transmission, approximately six feet, is well within the close contact distance between the surgeon and the patient that is required for physical examination, talking to the patient during history taking or obtaining consent, or the short distance between patient and provider during operative interventions.

Conclusion

Infection with the influenza virus poses a heavy inflammatory and immunologic burden. Complications of influenza infection can be devastating and long lasting. Surgical patients are in the eye of the perfect storm with the combination of factors including surgery-induced immune suppression, immune modulating comorbidities and medication, age-induced immunosenescence, as well as the large number of surgical healthcare workers who may act as viral shedders and transmitters. Older patients are at greater need for a variety of operative intervention as well as perioperative caregivers including surgical staff, rehabilitation personnel, and even nursing care facilities. It is essential that everyone who cares for surgical patients during influenza season take as much care as possible to avoid being potential influenza virus transmitters, especially around the elderly surgical population.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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