- Top of page
- Materials and methods
Acute respiratory tract infection (ARTI) is a major cause of morbidity and mortality worldwide. Throughout the winter season, many children are hospitalized due to respiratory infections, primarily caused by influenza virus, adenovirus, respiratory syncytial virus (RSV) and human metapneumo virus (hMPV). The influenza virus is a negative-sense, single-stranded RNA virus that contains eight gene segments encoding 12 proteins. It causes a clinically distinct, systemic illness, typically characterized by abrupt-onset fever, headache, myalgia, and malaise. Similar clinical characteristics have been detected following hMPV infections.[3, 4] hMPV has a negative-sense single-stranded RNA genome, containing eight genes, encoding nine different proteins. RSV has a negative-sense single-stranded RNA genome, encoding 10 subgenomic mRNAs, which are translated into 11 known proteins, and is the most common cause of lower respiratory tract infections in infants up to 1 year of age. In contrast to the aforementioned viruses, adenoviruses are non-enveloped, double-stranded DNA viruses that contain 12 viral proteins. Adenovirus infections are observed throughout the year and are considered one of the most common causes of upper respiratory tract infections.
Influenza infections can be life-threatening, mainly among the elderly, yet present a risk for the entire human population in the wake of influenza pandemics. Four major pandemic outbreaks have occurred in the last 100 years: the Spanish Flu pandemic (1918–1920, H1N1), the Asian Flu (1957–1958, H2N2), the Hong Kong Flu (1968–1969, H3N2), and the A(H1N1)pdm09 Flu (2009, H1N1). The A(H1N1)pdm09 virus was first detected in Mexico and subsequently spread to over 214 countries. In Israel, the virus circulated in two phases: from April 2009 until March 2010 and from October 2010 until March 2011. During 2012, only a handful of A(H1N1)pdm09 infections were reported.
The pandemic caused by the A(H1N1)pdm09 strain provided us with a unique opportunity to study the relationship between A(H1N1)pdm09 infection and infections caused by other respiratory viruses. While this relationship has been investigated by others,[9-11] these studies focused on the impact of A(H1N1)pdm09 on other viruses during 2009–2010, when the virus first appeared. Here, we assessed the effects that the A(H1N1)pdm09 had on other respiratory viruses when it first appeared and later, when it became a seasonal influenza virus.
- Top of page
- Materials and methods
The presented analysis provides several important, time-dependent findings that are associated with the pandemic A(H1N1)pdm09 virus. The A(H1N1)pdm09 infection, which was first noted in Israel in 2009, circulated in the country in 2009 and 2010–2012. In 2009, a biphasic pattern of infection was observed, with peaks of infection during weeks 22–30 and weeks 45–49. In contrast, in 2010–2012, only one peak of infection was detected, during weeks 3–5. Biphasic infection patterns observed for the A(H1N1)pdm09 infection in 2009 were reported by others [20, 21] and were also observed during the 1918 and 1968 pandemics, and may correlate with the school year and weather patterns. Indeed, the first 2009 peak was observed in Israel during warm weather, at the end of the school year, while the second peak was observed at colder temperatures at the end of the summer vacation.
The A(H1N1)pdm09 infection patterns differed between 2009–2010 and 2010–2012, with more patients being affected in 2009–2010, and with a greater impact on co-infection with adenoviruses, hMPV and RSV during its first phase of appearance. These disparities may have evolved from immune protection, which became more accessible between the two infection phases. In 2009, the A(H1N1)pdm09 virus was new to the population, and therefore ,individuals of all age groups were infected; however, in agreement with other reports, the elderly population was less infected with the virus. In contrast, by 2010–2012, around 50% of the population had already developed immunity against A(H1N1)pdm09. During this round of infection, 44% of the patients were children under the age of 10, 58% of which were infants under the age of 1 year, born after the 2009 A(H1N1)pdm09 infection had already declined. Similar differences in the age groups affected by A(H1N1)pdm09 have been described before. We therefore suggest that the changes observed in seasonality and age distribution of the A(H1N1)pdm09 infection reflects its evolution from a pandemic to a seasonal virus. Indeed, 75% of the hospitalized patients infected with A(H1N1)pdm09 in 2010–2012 suffered from comorbidities, whereas in 2009–2010, only 48% of the hospitalized patients had additional diseases. Furthermore, in 2009–2010, the A(H1N1)pdm09 virus was the main influenza virus strain circulating in the country, replacing the previous seasonal influenza A, H1N1.
An additional interesting observation is that the A(H1N1)pdm09 virus was dominant over other influenza viruses, manifested by an influenza virus-free lag period in the winter season of the 2010–2011. While the reasons accounting for this lag period are unclear, it can be explained by a potential general anti-influenza virus immunity in the population, triggered by the 2009–2010 A(H1N1)pdm09 infection, that prevented subsequent infections in 2010–2011. In the beginning of 2011, the seasonal influenza and A(H1N1)pdm09 infections were noted at the same time, an observation also seen in other countries.[25, 26] In addition, like in other countries, the only seasonal influenza A observed as the appearance of the A(H1N1)pdm09 was seasonal H3N2, while the seasonal H1N1 has disappeared altogether since then. The dominance of the A(H1N1)pdm09 infection did not affect co-infection with RSV and adenovirus, which is the most common co-infection.[28, 29]
We also observed that infection with the A(H1N1)pdm09 virus influenced the infection pattern of other respiratory viruses, especially in 2009. The time of the infection with other respiratory viruses changed and hMPV and adenovirus infections were more frequent only after the A(H1N1)pdm09 infection had declined. Increased hMPV infection rates were noted in infants <1 year of age. Furthermore, in agreement with other studies,[30, 31] following the A(H1N1)pdm09 infection, RSV infections were detected later than usual. We also observed, as reported in Hong Kong, that children between the ages of 1–5 years were less frequently infected with RSV B following the decline of the A(H1N1)pdm09 infection. The reasons for this decline are not completely understood, but can plausibly be due to the generation of a cross-reactive specific and non-specific anti-RSV B immunity following the A(H1N1)pdm09 infection. Indeed, it has been well established that influenza virus-infected cells produce interferon and other cytokines.[32, 33] Other studies have suggested that the impact of the A(H1N1)pdm09 infection on RSV immunity may be the result of increased hygienic measures implemented following the pandemic.[30, 31] Regardless of the reasons accounting for the reduced RSV infection following the A(H1N1)pdm09 pandemic, these results suggest that pandemic influenza infections may provide some minor benefits by reducing infection rates of other viruses.
In conclusion, we demonstrate here that the A(H1N1)pdm09 virus significantly affected infections with other respiratory viruses, when it first appeared in 2009. We further showed that in subsequent years, the A(H1N1)pdm09 virus lost its dominancy, suggest to be due to its evolvement from a pandemic virus into a seasonal influenza virus.