Influenza Disease Background

Introduction

The clinical spectrum of influenza ranges from asymptomatic infection to primary viral pneumonia that may progress to death. Patients presenting with influenza-like illness (ie temperature of 37.8°C, cough and/or sore throat, and absence of a known cause other than influenza) might be infected with different types of influenza virus (eg avian influenza [H5N1]) as well as other respiratory pathogens. A high index of suspicion is needed to recognize influenza in hospitalized patients. Pneumonia is the most common complication of influenza virus.

Epidemiology

According to the World Health Organization (WHO), seasonal influenza spreads rapidly, especially in crowded places. It occurs mainly during the winter in temperate areas, but it may occur irregularly throughout the year in tropical areas. Avian influenza on the other hand, although rare, has been reported sporadically. It can be transmitted through direct contact with an infected animal or a contaminated environment. 

Seasonal influenza caused approximately 3 to 5 million severe cases, and 290,000 to 650,000 resulted in death. Most of the mortality is among those ≥75 years old and those living in sub-Saharan Africa and Southeast Asia. Seasonal epidemics occur annually in the United States (US). From 2010 to 2020, an estimated 9 to 45 million illnesses were reported in the US. Following the 2009 influenza A (H1N1) pandemic, several population-based surveys have reported approximately 5,000 to as high as 56,000 deaths annually from 2010 to 2014 in the US. Meanwhile, avian influenza A (H5N1) had 874 cases globally causing 458 fatalities from 2003 to 2023.

In Asia, one study utilizing the WHO database reported that there was a total of approximately 700,000 confirmed cases of influenza from 2010 to 2017 while another study using similar data reported that influenza causes more than 130,000 cases annually. Several cases of avian influenza have been reported in the Asia-Pacific region, totaling 1,568 cases of A (H7N9) since 2013, 244 cases of A (H5N1) since 2003, 87 cases of A (H9N2) as of 2015, 84 cases of A (H5N6) since 2014, three cases of A (H3N8), two cases of A (H10N3), and one case of A (H7N4) since 2018. 

According to a study that employed the Chinese National Influenza Surveillance Network, cases testing positive for influenza ranged between 0.1 to 10.6% in Mainland China from 2020 to 2021. More recently, a total of 110,241 influenza-positive cases were tallied as of May 2023, and a total of 55 cases of avian influenza A (H5N1) resulting in 32 deaths were reported from 2003 to 2023 in China. In Hong Kong, data from the Center for Health Protection reported that seasonal influenza remained active and continually increases from 0.3 to 5.2 influenza-like illness cases per 1,000 consultations in general clinics and 15.4 to 49.3 influenza-like illness cases per 1,000 consultations in private clinics in 2023. In South Korea, 10 to 20% of adult Koreans are infected by seasonal influenza annually; although more recently, only a total of 450 influenza-positive cases were tallied by WHO as of May 2023. 

Estimates from 2010 to 2019 in India reported more than 100,000 cases and 8,000 deaths. Like other countries, cases declined in 2020 due to the coronavirus disease of 2019 (COVID-19) pandemic, tallying only approximately 2,700 cases and 44 deaths. 

In the Philippines, the mean annual influenza incidence was estimated at 5.4 per 1,000 individuals in urban areas. A study utilizing the data from the Philippine Statistics Authority from 2006 to 2015 concluded that influenza was estimated to cause more than 5,000 deaths annually. Although, more recently, only a total of 83 influenza-positive cases were tallied by WHO as of May 2023. In Thailand, the overall incidence was reported to be 178 cases per 100,000 populations causing approximately 300 to 7,000 deaths annually. Based on the most recent report by WHO, there were already 3,118 influenza-positive cases in Malaysia, 1,002 cases in Singapore, and 12 cases in Vietnam as of May 2023. Avian influenza A (H5N1) was also reported in Vietnam from 2003 to 2023 tallying 128 cases and 64 deaths. 

Due to the COVID-19 pandemic, influenza infection rates likewise declined especially in 2020 because of improved preventive measures, travel restrictions, and immunization.

Etiology

Seasonal Influenza

The types of influenza viruses known to infect humans are types A, B, and C. Types A and B are the main causes of influenza outbreaks. 

Avian Influenza

Avian influenza is also known as bird flu and is caused by type A strains of the influenza virus. Influenza A(H5N1) is a subtype of the type A influenza virus and is the cause of the outbreaks of avian influenza worldwide. Human transmission of another subtype, influenza A(H7N9), was first reported in 2013. 

Although it is generally considered to be a disease that affects only birds, avian influenza viruses can infect several animal species (eg pigs, horses, seals, whales) but do not usually directly infect humans or circulate among humans. Human transmission can be caused by exposure to droplets and direct or indirect contact with feces or nasal secretion of the sick animal. Human-to-human transmission can possibly occur among close contacts.

Pathophysiology

The influenza virus (particularly influenza type A) contains surface proteins called hemagglutinin and neuraminidase. The aerosolized influenza virus enters the upper respiratory tract and then spreads into the airways infecting the surface of respiratory epithelial cells via hemagglutinin. The influenza virus binds to surface receptors and enters the host cells via endocytosis, where viral replication ensues until such time the host cells get destroyed. Neuraminidase helps release and spread the virions by cleaving the bonds that hold the virus together. The immune system via hemagglutination inhibition antibodies of most individuals is powerful enough to make the condition self-limiting. However, for some susceptible individuals, immune reaction and excessive cytokine formation may cause severe manifestations.   

Antigenic drift involves minor mutations in hemagglutinin and neuraminidase glycoproteins which may enhance the antigenicity of the virus causing seasonal epidemics. Meanwhile, antigenic shift involves abrupt, major mutations in such glycoproteins, probably causing genetic recombination between viruses that affect humans and/or animals, causing the formation of a novel influenza virus which can cause pandemics.