INTRODUCTION
With the advent of the SARS-CoV-2 pandemic, influenza has taken a back seat with regard to transmissible viral infections. This has been exacerbated by a significant reduction in cases in the winter of 2020 most probably because of social distancing, hand washing and use of masks.(1) This, however, does not necessarily bode well for future winters, in that less exposure potentially means less immunity and more intense outbreaks, particularly since South Africans are notoriously reluctant to take vaccines, as reflected in a sample of private health-insured subjects.(2) Uptake amongst the uninsured population is probably lower than that of the private sector and the causes of continued “vaccine hesitancy” are multifactorial. These include vaccine accessibility, perceived or actual efficacy, fear of adverse effects, belief that it is not necessary, or that the vaccine makes one sick, or that influenza is a mild disease from which one recovers rapidly.(3,4) There is unfortunately also increasing distrust of vaccines, in particular, that is gaining traction amongst the affluent in society and which is the result of fake news that expounds on ill effects of vaccines. This has already led to outbreaks of vaccine-preventable diseases such as measles and polio with considerable mortality and morbidity. It is of particular concern that healthcare workers globally are themselves often reluctant to accept vaccination despite it being mandatory in many countries, including South Africa.(5,6)
The economic impact of influenza is proportional to the disease burden and the prevalence of risk factors for severe disease in any environment. In South Africa, this is estimated to be considerable. The local risk groups, as defined by the National Institute for Communicable Diseases (NICD), are broad and include: pregnancy (including the post-partum period); HIV–infected individuals or those with tuberculosis; persons aged ≥65 years; those ≤18 years of age and receiving chronic aspirin therapy; the morbidly obese (i.e. BMI ≥ 40); young children (particularly ≤2 years of age), and persons with chronic diseases regardless of age, inclusive of pulmonary diseases such as asthma and chronic obstructive pulmonary disease (COPD), immunocompromise, cardiac diseases (except for hypertension), diabetes mellitus, renal or hepatic disease, neurologic or neurodevelopmental conditions or haemoglobinopathies, such as sickle cell disease.(6)
Whereas many of these factors are obvious, some may not be, and in particular pregnancy, where there is often concern that vaccination may be harmful to the mother or foetus or both. However, on the contrary, there is significant benefit to both. Similarly, there is also a belief that vaccination may be harmful or that it is not necessary for the very young. This is also incorrect as the mortality rate from influenza is highest in this age group.(7,8) There are in the region of 11,800 influenza-related deaths and 47,000 episodes of related severe acute respiratory illness annually with 22,481 hospitalizations in South Africa.(9,10) The high prevalence of risk factors, including tuberculosis and HIV, exacerbates the situation and this increases the need for vaccination or prevention by other means. As far as the global impact is concerned, seasonal influenza results in approximately 3–5 million cases of severe disease and 290,000–650,000 deaths annually.(11)
Clinical impact of influenza
One of the reasons for this is that while influenza may cause a severe viral pneumonia, it also predisposes to bacterial, fungal and other co-infections, caused most commonly by organisms such as S. pneumoniae and S. aureus.(12) The synergistic effects of influenza and S. pneumoniae are multifactorial and relate to factors such as damage by influenza to the respiratory epithelium with exposure of the basement membrane, up-regulation by influenza of molecules to which the pneumococcus adheres, and impaired function of immune cells, including macrophages and neutrophils.(13–16) This phenomenon of viral-bacterial synergism was apparent in the 1918 pandemic, where a significant number of cases were secondarily infected with bacteria and many of these bacterial infections were the ultimate cause of death.(17) Similar findings have also been documented during subsequent influenza pandemics, most recently the H1N1-2009 pandemic. Although clearly the mortality from these co-infections in the case of H1N1 influenza A infection was much less than that during the 1918 pandemic, because of the current availability of antibiotics, they were nonetheless significantly associated with severity and mortality.(18,19) One systematic review of the role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza A (H1N1)pdm09 found that whereas few studies reported on bacterial complications, those that identified secondary bacterial infection most commonly reported secondary infections with S. pneumoniae in almost one in four cases, and noted that this was associated with serious outcomes such as need for ICU admission and death. The authors concluded that prevention and treatment of secondary bacterial infections should be an important part of pandemic influenza planning.(20) More recently, other organisms, such as aspergillus, have also been implicated and should be considered in patients that fail to improve or have elevated fungal biomarkers.(21)
Complications of influenza also include myocardial injury with various studies demonstrating that both influenza and S. pneumoniae infections have a temporal relationship to acute myocardial infarction, with adjusted incidence ratios (IRs) of 5.98 and 9.80, respectively. This same relationship also applies to stroke in which the IRs are 12.3 and 7.82, respectively.(22) Another study which assessed the incidence of hospitalization for acute myocardial infarction pre- and post-influenza infection found an increase in the rate in the 7 days immediately after the infection which was six times greater than what had occurred in the 12 months before or after.(23)
Coupled with this have been intriguing reports that influenza may be also related to the development of Alzheimer's disease. Two abstracts presented at the Alzheimer's association international conference, 2020, indicated that at least one influenza vaccination was associated with a 17% reduction in Alzheimer's incidence and more frequent vaccination with an additional 13% reduction.(24) Similarly, vaccination against pneumococcal pneumonia between the ages 65 and 75 years reduced Alzheimer's risk by up to 40%, depending on individual genes.(25)
Whereas the global and local mortality and comorbidity are considerable, the economic burden from Influenza is similarly substantial, particularly for a developing country. This was evaluated for the years 2013–2015 in South Africa and published in 2019 where it was estimated that the mean annual cost was $270.5 million and that this was contributed to by both government (41%) and individual (15%) expenditure, and indirect costs including absenteeism (44%). Severe acute respiratory illness accounted for a considerable portion of the total economic and health burden at 21% of total cost.(26)
Prevention strategies
Given the mortality statistics and the comorbidity associated with influenza, the primary aim would be prevention. This would require there to be a freely available and effective vaccine and a population that was willing to take it. Overall, the efficacy of influenza vaccine varies according to the match between the circulating influenza strains and the influenza strains included in the vaccine in any given season. The influenza virus undergoes seasonal “drift” which renders previous vaccines less effective. In general, two influenza A strains and one or two influenza B strains are prevalent each winter and all can cause severe disease. The need to “guess” which strains are likely to be prevalent in any given season and the phenomenon of antigenic drift results in most seasonal vaccines being only moderately effective. However, if one considers the size of the problem, even a vaccine which is only 30% effective will have a large impact. In a recent study which investigated the impact of influenza vaccine in the United States for the 2017–2018 season, overall efficacy was estimated to be only 38% (CI, 31%–43%), which was similar to that of previous seasons.(27) However, despite this, the authors calculated the number of health outcomes averted to be more than 7 million illnesses, 3.7 million medical visits, more than 100,000 hospitalizations, and approximately 8000 deaths. In addition, as pointed out in a recent editorial if one includes the reduction in transmission by vaccinated individuals, this effect is up to 2-fold greater.(28)
Perhaps under-appreciated is the fact that even if one contracts influenza post-vaccination it is likely to be less severe. A study in 2014 showed that the vaccine reduced the risk of intensive care admission in children by 74% during the seasons from 2010 to 2012, and a more recently published study showed that vaccination among adults reduced risk for ICU admission by 82%.(29,30)
One final benefit of the influenza vaccine is that in the era of increasing antimicrobial resistance vaccination dramatically decreases antibiotic prescription.(31) This cannot be emphasized enough to both doctors and the public as we enter the post-antibiotic era.
Whereas the ideal would be for the whole population from 6 months of age and upwards to be vaccinated, this is unlikely to occur for the reasons given above. There should, however, be increased publicity for the need for vaccination, and health care providers should be sensitized to the need to discuss this with all of their patients. The most receptive group, however, are likely to be those that are at risk for more severe disease, and they and their close contacts should receive special attention in order to ensure that they receive yearly vaccination.(32)
Given the fact that the COVID-19 pandemic may still be with us during the next winter season in South Africa, and recognizing the intense synergistic interaction between influenza and pneumococcal infections described above, it would be prudent not only to optimize influenza vaccination, “to maintain the integrity of the healthcare system” but also to consider the additional benefit of enhancing pneumococcal vaccination, particularly in high-risk cases, as has been suggested previously by others.(33,34)
CONCLUSION
The importance of influenza as a disease has been eclipsed by the SARS-CoV-2 pandemic. However, as demonstrated in many studies, it still causes an immense public health burden in terms of morbidity and mortality. Importantly the use of antibiotics is also increased thus driving antimicrobial resistance, while simultaneously having an enormous economic impact, both nationally and globally. It is critical that we prepare appropriately for the next influenza season in order to mitigate the severity of yet another viral assault.