Introduction
Infectious diseases continue to be one of the largest burdens on humankind. Despite the availability of modern medicine, infectious diseases remain the number one cause of mortality. Two of the most common human respiratory infections are those caused by
Mycobacterium tuberculosis and influenza virus [
1]. Regardless of the availability and accessibility of effective treatment protocols, tuberculosis (TB) ranks second in the list of common infectious diseases. Similarly, even with the availability of preventive interventions and vaccines, influenza infections cause significant morbidity and mortality each year around the world [
2]. Pakistan ranks 5th amongst countries for burden of TB, with an estimated 510, 000 new cases and approximately 15,000 TB drug resistant cases every year, accounting for 61% of the TB burden in the Eastern Mediterranean Region of World Health Organization (WHO). In 2021, tuberculosis was the 13th most common cause of death and the second leading infectious killer after COVID-19 above HIV/AIDS [
3].
Influenza is a serious threat to human health, especially to those in risk groups, including the immunocompromised, elderly, and very young adults [
4]. The WHO estimates that influenza-related respiratory illnesses alone cause 3–5 million cases of severe sickness and 290,000-650,000 fatalities worldwide each year [
5]. Pakistan has a high burden of infectious diseases due to its favorable climate and population density (the population of Pakistan is 225 million)[
6]. Co-morbidity with respiratory viruses, including influenza A, cause a varying degree of morbidity in TB patients compared to the general population [
7]. For example, influenza can weaken the innate immune responses to secondary bacterial infections by impairing T-cell immunity [
8].
Increased mortality has been seen in TB patients following influenza infections [
9,
10]. A sharp decline in TB prevalence was observed after the 1918 Spanish influenza pandemic, possibly due to higher mortality in co-infected patients. Influenza virus pandemics have led to selectively increased mortality among those who suffer with tuberculosis [
11]. Individuals with pulmonary tuberculosis (PTB) are at a higher risk of being infected with the influenza virus which may lead to chronic lung disease, immunosuppression and even death. A better understanding of the co-infection of influenza and TB is crucial for policymakers to prioritize the target population for influenza vaccination. Data on the burden of influenza among TB patients is very limited especially from lower and middle income countries. The present study, therefore aimed to estimate the burden of influenza A (H1N1)pdm09 among TB patients with a goal to generate data to improve strategies for reduction of mortality associated with TB.
Discussion
Influenza and tuberculosis both cause significant morbidity and mortality worldwide [
14]. Individuals with pulmonary tuberculosis (PTB) are more likely to get a severe influenza virus infection, which can cause chronic lung disease, immunosuppression, and death [
15]. A better understanding of the co-infection of influenza and TB is crucial for policymakers to prioritize the target population for influenza vaccination [
16]. Data on the burden of influenza among TB patients is very limited. Therefore, this study aims to estimate the burden of the influenza A (H1N1)pdm09 virus infection amongst TB patients compared to the general population.
In the current study, the proportion of influenza A (H1N1)pdm09 positive cases were higher in males compared to females in the TB cohort. Similarly, in the comparison group, men had more influenza A (H1N1)pdm09 positive cases than women whilst the drivers of this are not known, men in Pakistan usually participate in more outdoor activities and are at a higher risk of exposure to diseases like influenza through close interaction and contact with people who are sick, or contaminated objects or surfaces [
17]. Women have also been shown to have a higher compliance with hygienic practices such as hand hygiene/washing, which may have decreased the likelihood of viral infections [
18]. Many studies have shown that females have a greater adaptive immune system than males [
19‐
22]. In general, females have higher levels of innate immune cell activity than males, especially at reproductive ages. These cells include dendritic cells (DCs) and macrophages, as well as the overall general inflammatory response [
21,
23]. Furthermore, females have greater T-cell counts i.e. CD3 + and CD4+, as well as a higher CD4 + and CD8 + ratio, than males, whereas males have higher frequencies of CD8 + T cells and NK cells [
24]. On the other hand, at the time of an influenza A virus infection, testosterone reduces inflammatory monocyte infiltration and pulmonary inflammation [
25]. These all provide some mechanistic possibilities for the findings of the current study.
Influenza viruses can cause infection in individuals of any age. However, age groupings can have an impact on the disease’s epidemiology [
26,
27]. In our study, adults in the age category 18–43 had the highest percentage of influenza A (H1N1)pdm09 positivity in both groups i.e. TB cohort and comparison group. Previously, a higher positive proportion of influenza A cases were detected in adults ranging from 16 to 30 years of age in a sentinel surveillance of ILI and SARI patients in Lahore, Pakistan [
28]. Through significant physiological and behavioral changes that take place throughout life, age may potentially have a varied impact on the outcome of influenza virus infection in males and females [
29]. In the present study, the incidence of influenza A virus was higher in the TB cohort in comparison to the general population. Similarly previous studies have reported a higher proportion of influenza A virus in TB infected individuals in comparison to the control group [
30]. Variations in these estimates could be due to different study designs and/or the characteristics of the population studied.
We observed an incidence rate higher in our TB cohort group in comparison to the general population. Similarly earlier studies have also reported a lower incidence rate amongst the general population [
31], [
32]. The WHO predicted that the pandemic virus would continue to circulate at the same time as seasonal viruses and could lead to outbreaks [
33]. Influenza virus pandemics have led to selectively increased mortality amongst those who suffer with tuberculosis [
9,
10] A sharp decline in TB prevalence was observed after the 1918 Spanish influenza pandemic, possibly due to higher mortality in co-infected patients compared to the general population [
11]. People at risk have a significantly higher chance of developing severe influenza and influenza complications [
34], often due to suppression of their immune systems which can reduce the ability of the body to control infections. Furthermore, this co-infection could deteriorate the underlying illness, increasing the risk of hospitalization and death [
35,
36].
Of our enrolled individuals, only 1.32% of the TB cohort and 3.95% of the comparison group received an influenza vaccination in the previous year. This uptake of the influenza vaccine was lower than reported in the non-immunocompromised (59%) and immunocompromised individuals (25%) in one study in the United States [
37]. Vaccination remains the most important and effective primary prevention strategy for reducing the influenza burden in both immunocompromised and healthy populations [
37]. Our study has two main limitations. Firstly, it was restricted to the influenza A virus only, and other respiratory pathogens i.e. bacteria and viruses were not studied. Secondly, Latent Tuberculosis was not detected in the general population due to financial constraints.
Influenza poses a serious threat to public health, and immunocompromised patients constitute a vulnerable and high-risk population. More research must be done to develop prevention methods to reduce the burden of influenza virus infection in immunocompromised patients including those with TB. The data generated through the current study should be utilized by health authorities to prioritize influenza vaccination of TB infected individuals as part of a strategy to reduce the burden of excess mortality in this vulnerable population.
Acknowledgements
The authors would like to thank all participants for giving data, as well as the hospital administration for granted access to all patients. We’d also like to thank Dr. Richard J. Webby, PhD, (St. Jude Children’s Research Hospital, Memphis, TN, USA) for editorial suggestions and English language editing.
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