Pandemic Potential of a Strain of Influenza A - Research Paper Example

? Pandemic Potential of a Strain of Influenza A (H1N1 Early Findings The rise of a new strain of influenza A referred to as A (H1N1) virusin February 2009 prompted health authorities in to discovering the pandemic potential of this strain. Although this pandemic was declared to be over in August 2010, future pandemics cannot be ruled out due to certain characteristics of the virus. Therefore, it’s potential to cause a pandemic needs to be assessed. This paper aims to do this. In this paper, we first analyze the H1N1 outbreak timeline followed by the analysis of influenza A (H1N1) itself. Since this paper aims to study the pandemic potential of this strain, we will take a brief look at the history of pandemics followed by a brief look at the phenomenon of pandemics. Following that will be a detailed study of each of the factors that affect pandemics which include transmissibility, genetic diversity, severity, preventive measures and treatments. Introduction Health authorities across North America were set into frenzy when it was discovered in February 2009 that a novel strain of Influenza A had been found in the diseased population of a small town in Mexico. This virus was earlier referred to as H1N1 but subsequent studies showed that this was a reassortant form of 1918 HIN1 and with this discovery came the possibility of the rise of a new strain of influenza that could behave in an unpredictable manner. The general media came to call this disease Swine Flu and the new strain was termed by scientists as A (H1N1) virus. Within a couple of months, countries around the globe began to report cases of swine flu and on 11th June 2009, WHO declared it to be a pandemic. Containment programs began across the globe which included isolation setups for confirmed or suspected cases, restricted travel and vaccination weeks. Studies were undertaken to find out the genetic and antigenic characteristics of the virus and transmissibility and virulence were looked upon in great detail in trying to predict the duration and severity of this pandemic. Although a lack of data collection networks in underdeveloped countries led to an inability to estimate the actual number of people affected, studies were able to predict that this pandemic will be mild and short-lived well before the pandemic was declared over in August 2010. However, assessing the pandemic potential of this relatively new strain of influenza A, H1N1 is extremely important in order to predict a pandemic-in-waiting. This is best possible by studying the information collected during the pandemic and this is what this paper aims to achieve. Pandemic Potential of a Strain of Influenza A (H1N1): Early Findings The influenza A strain of H1N1 also known as Swine flu, showed its first outbreak in early 2009 with the WHO declaring it to be a pandemic in June 2009. This call was taken back in august 2010 and the influenza pandemic was declared to be over. A look at the chronological developments in this pandemic is useful in assessing the trends that this pandemic has followed. Chronology of H1N1 pandemic Around 15th February 2009, the first case of this outbreak was reported in the town of La Gloria, Mexico and this was followed by 60% of the town’s population being affected by a respiratory illness of unknown nature. While the local authorities attributed this to H3N2 strain of influenza, at least one of these cases was reported to be caused by HIN1 strain. On March 17th 2009, the first case of flu due to H1N1 was confirmed in a Mexico. Meanwhile, authorities like CDC in USA continued to report on the new influenza activity in 35 states of USA but reported that the activity had not reached the point where it could be labeled an epidemic. On 1st of April 2009, the first confirmed case of ‘swine flu’, as it came to be called generally, was reported in a ten year old boy living in California. The next day, the Mexican authorities confirmed the first proven case of H1N1 in a four year old boy. On 12th April, the first known fatality of the outbreak, a 39-year old woman suffering from viral pneumonia, was reported. While the CDC investigated the occurrences of influenza-like illnesses in California and Texas, World Health Organization issued its first Disease Outbreak Notice about swine flu on 24th April 2009. Within the next three days, WHO’s Emergency Committee raised the pandemic alert to phase 4. The European Union advised its nationals of European countries to avoid travelling to USA and Mexico but new cases emerged in several countries including Spain, Canada, United Kingdom, New Zealand, Israel, Austria, Germany, Switzerland, France, Ireland and China. In a confirmed case of swine flu in Netherlands, the patient was a three- year old child who had returned from Mexico but her parents were found negative for H1N1 when tested. These reports also included the first death outside Mexico attributed to H1N1 influenza. This was a 23-month old Mexican child who was hospitalized in Texas. By 28th April, four out of six regions of WHO were had confirmed reports of swine flu. On 29th April 2009, WHO raised the pandemic alert level from phase 4 to phase 5. Cases affected by this disease became apparent as far as India and Polynesia and a strong link between schools and disease was noted. On June 11th 2009, WHO raised the pandemic alert level to 6 confirming the influenza pandemic and indicating extremely high levels of transmission of virus. By this time WHO confirmed 29,669 cases of Influenza A and 145 related deaths across the world. On 29th June 2009, the first case of resistance to Oseltamavir was discovered in Denmark. This drug was initially the treatment of choice for H1N1 Influenza. On 23rd July 2009, the Arab League agreed upon new regulations for Hajj under which anyone under the age of 12 or over the age of 65 with a chronic illness was not allowed to perform Hajj. On 27th August 2009, WHO issued a warning about turkeys that were infected by H1N1 at a farm in Chile. This was the first instance of zoonosis and signified genetic reassortment. Over the next one year, the pandemic reached its peak in South America, North America and Europe and later returned to baseline levels while a moderate pandemic occurred in Asia and Middle East and reached baseline levels fairly quickly. By 6th August 2010, WHO declared that 214 countries had reported cases affected by influenza A strain, H1N1, with a total of 18449 deaths (World Health Organization). The exact number of people affected might never be known. On 10th August 2010, WHO announced the influenza pandemic to be over and the activity of influenza to have returned to baseline, seasonal levels. There were allegations against WHO raised from several quarters according to which, WHO had hyped up the issue and provided ‘fear and confusion’ instead of ‘immediate information’ (MSNBC). How far these allegations were true is a topic of debate but in trying to understand the pandemic potential of influenza A stain, H1N1, the study of the phenomenon of pandemic itself as well as the characteristics of the virus and how far they overlap with each other is very important. Pandemics: a brief review A pandemic is defined as an infectious epidemic that spreads over a large geographical area such as a continent. It differs from an epidemic in terms of the area over which it affects people. Not all epidemics become pandemics but pandemics are always an escalation of epidemics. In 1999, WHO divided the development of a pandemic into six phases. These are as follows (HKPRDHU). period Phase description Intrapandemic period Phase 1 No new influenza strain is detected in humans. However, a circulating animal strain poses a very low risk of infection in humans. Intra pandemic period Phase 2 No new strain is detected in humans. However, a circulating animal strain of influenza virus is posing a significant risk of human disease. Pandemic alert period Phase 3 Human infections with a new strain with no evidence of human-to-human spread. May show a rare case of spread to a close contact. Pandemic alert period Phase 4 Small cluster(s) with restricted human-to-human transmission indicating that the virus is not well adapted to humans. Pandemic alert period Phase 5 Larger cluster(s) but restricted human-to –human transmission. This indicates that the virus may be adapting but is not yet fully transmissible. This also indicates significant pandemic risk. Pandemic period Phase 6 Increased and persistent transmission in general population Postpandemic period Return to interpandemic period The time between phase 6 and postpandemic period is punctuated by a post-peak period. This period denotes the progress of the pandemic past its peak followed by a drop. Although a decrease in the pandemic activity is evident, the possibility of a future wave cannot be measured or ruled out. Throughout history, pandemics involving several diseases have been recorded. These diseases include plague, cholera, influenza, small pox, tuberculosis and HIV/AIDS. There have been three pandemics of plague. The first one was The Plague of Justinian that started in Egypt and spread to Europe killing nearly half of its population from 541 to 750 BC. The trend of travelling from European lands to far off lands is considered to be a very important factor. The last of these pandemics started from China in mid-19th century and spread to India and as far as the USA. Again travel was an important factor. Cholera has had 8 pandemics all of which are said to originate in the Asian subcontinent but spread as far as Far East Asia and Polynesia. The most recent one took place during the period 1991-2002. The pandemic of small pox was responsible for 300-500 million deaths across the world in 20th century until a very affective vaccination campaign was launched against small pox and in December 1979, WHO declared small pox to be completely eradicated. The tuberculosis pandemic occurred in the 19th century and by late 19th century, 70 to 90 % of urban residents of Europe and North America were suffering from TB. Around 40% of deaths in the urban areas were attributed to TB during this time (The President and the Fellows of the Harvard College). This disease still remains endemic in developing countries. The current pandemics include the 2009 flu pandemic and the HIV/AIDS pandemic. The HIV/AIDS pandemic began around 1969 and quickly gripped North and South America followed by Africa and Asia. Currently, India has the highest population of patients infected by HIV. Four influenza pandemics have occurred so far and these include the Spanish flu in 1918, the Asian flu in 1957 and the Hong Kong flu in 1968-1969. The 1918 flu pandemic was caused by H1N1, the Asian flu pandemic by H2N2 and the Hong Kong flu pandemic by H3N2. All of these were subtypes of Influenza A and possessed a hemagglutinin (HA) against which there was no immunity. Similar was the case with Pandemic H1N1/09 and a chronological account of it has already been given. What remains to be seen are the factors that led to these pandemics and whether similar trends are seen in the spread of H1N1 strain so that the potential of a pandemic can be determined. Pandemics occur due to three basic reasons. A disease emerges within a population which is completely new to the population The agent has the ability to cause infection in humans leading to serious illness. This ability is called virulence. The agent spreads easily among humans while maintaining its viability. This ability is called transmissibility. Findings regarding each of these three factors will be discussed in the following sections. Genetic and antigenic variability of A (H1N1) virus A very important factor in determining whether a strain has the potential to cause a pandemic is the degree to which that strain is alien to its surrounding population. This could either be through the introduction of an agent that is completely new to a certain geographical area or it could be genetic variations that render that organism as relatively new to a population. In the case of H1N1 it is the second case. H1N1 was first isolated from swine in 1930 and had very strong resemblance to one of its ancestors 1918 A(H1N1) virus in terms of its antigens. From 1930 to 1998, the virus was antigenically stable until when it underwent a triple reassortment with A (H3N2) and an unknown avian strain that resulted in triple reassortant H3N2 (rH3N2). This strain was widely distributed in swine populations throughout North America and was later reassorted with the classic H1N1 giving rise to triple resonant swine A (H1N1). This variant was also found in Asian swine populations during that time. After 1999, the virus underwent several antigenic drifts that were occurring since 1918 but were at their peak in 1999 (Gavin J. D. Smith). However, the antigenic stability of the virus during this time led to a significant antigenic gap between the classical and the human seasonal varieties and this rings an alarm about a looming influenza pandemic. The antigenic drift during this time led to a 16-fold difference in the hemagglutinin inhibition (HI) assay compared to its pre-reassortment strains when measured with swine sera (Garten, Davis and Russel). These strains were also isolated from humans but these were rare instances. In April 2009, a previously unknown A (H1N1) virus was isolated from the Mexico and southern states of USA. This virus derives its NA and M gene segments from a Eurasian lineage, which was previously not found in this region and its PB1, PB2 and PA gene segments from swine triple reassortant lineage. Information regarding where this reassortment took place and for exactly how long this strain has been circulating in swine population is not known owing to poor surveillance of influenza virus. An analysis of each of the gene segments showed that they were 99.9% identical to the sequenced viruses that had led to outbreaks in the past (Garten, Davis and Russel). This shows that the cross –species introduction of the virus into human is either a single event or multiple events of viruses which are genetically similar. Antigenic analysis of the A (H1N1) virus shows that several amino acid substitutions have occurred at putative antigenic sites which have rendered this strain resistant to adamantine (Dyede, Xu and Bright) while sensitivity to oseltamivir, zanamivir and neuraminidase inhibitors was intact. Later on, the first case of oseltamivir resistance was isolated in Denmark. The virus’s adaptation to human hosts can be assessed using its molecular markers. A study of these molecular markers showed that the PB1-F2 protein, a characteristic feature of the 1918 virus and the highly pathogenic H5N1 virus, is truncated in A (H1N1) virus. Similarly, NS1 protein plays a key role in cell signaling pathways and the subsequent pathogenicity of 1918 virus and H5N1 virus. NS1 protein is also truncated in A (H1N1) virus. In spite of these differences, A (H1N1) virus has spread in human population and therefore its pathogenicity and biological markers are different from its ancestors. The surface glycoprotein HA plays a key role in initiating the formation of antibodies against infection. Therefore, they have a major role to play in effectiveness of vaccines against influenza. Studies show that A (H1N1) virus has several amino acid substitutions in HA but none of these substitutions have an antigenic effect and so the vaccines effective against other influenza strains are just as effective against A (H1N1) virus. Virulence of A (H1N1) virus In 1977, a mild epidemic of Influenza A (H1N1) virus occurred in the southern regions of USA. A study was conducted on 200 seronegative infants and children aged less than 4 years regarding the virulence of A (H1N1) virus and A (H3N2) virus. The study concluded that A (H1N1) caused insignificant illness in this age group (Wright, Thompson and Karzon). However, in the years following that outbreak, the A (H1N1) strain underwent several reassortments and antigenic drifts and new estimates of the virulence along with the factors behind the virulence of this strain is a key to understanding its pandemic potential as well as treatment and preventive modalities. The most important factor in determining the virulence of any disease is the case fatality ratio. This can be determined only when an accurate number of people affected by that disease and the number of deaths occurring due to that disease are available. In the case of Pandemic H1N1/09, the real number of people affected might never be known as a large proportion of facts will be lost in remote areas such as Mexico where surveillance is not very effective. However, WHOs figures show that a total of 18449 deaths occurred during the period between June 2009 and August 2010. As mentioned earlier, the high pathogenicity possessed by 1918 virus and H5N1 virus by intrinsic production of PB1-F2 protein and NS1 protein is absent in A (H1N1)virus since this strain lacks these proteins. However, A (H1N1) virus does cause infection which can range from a mild illness to severe distress and even death. Ina study conducted on virulence markers of A (H1N1) virus, it was concluded that the virulence of this strain is higher than the other seasonal influenza strains and that this virulence might lie in the mutations PB2-627 protein (Guang). The study also concluded that since A (H1N1) virus is highly susceptible to mutations and reassortments, the virulence markers for this strain are not clear yet. This means that not only does the virus have an extremely high potential of causing a pandemic but only regular surveillance can prevent this pandemic to be less severe in terms of infection and spread than the earlier influenza A pandemics. The signs and symptoms of H1N1 flu are very similar to that of flu caused by other strains. They include coryza, fever and generalized body pains and some patients may complain of diarrhea and neurological signs although these are very rare. Children less than five years of age are affected most particularly children with cerebral palsy, muscular dystrophy and neurodevelopmental delays (Morbidity and mortality weekly report). This mainly occurs because children with these disorders are unable to cough adequately preventing their airways from complete clearance. Other susceptible groups include women in their third trimester of pregnancy and people of any age with chronic illnesses such as diabetes, cardiovascular diseases, AIDS and asthma. A very unique characteristic of this strain is that it does not infect people over 60 years of age as readily as other influenza strains (Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza ). Virulence of A (H1N1) virus depends upon three factors. These include the interaction of the virus with the host cell, the interaction of the virus with the host and the population of the host (Baigent and McCauly). The most important of these is the interaction between the host cell and the virus which occurs mainly through HA. The viral hemagglutinin (HA) and neuraminidase (NA) interact with the host cells structure and sialyloligosacharide receptors binding the virus to the host cell and releasing virions inside it. HA facilitates the binding of the virus to the host cell which is then countered by the distribution of intracellular and extracellular host proteases. This is why HA is of extreme importance in the virulence of any influenza strain. When this influenza strain is susceptible to mutations and antigenic drifts as the A (H1N1) virus, the study of HA becomes extremely important. Studies have concluded that the HA of this strain has not been affected by amino acid substitution and that the vaccines against the rest of the influenza strain are just as effective against this strain. This also means that while antigenic and genetic virulence factors of A (H1N1) virus are still unknown, the vaccinations are still effective and therefore, the exact pandemic potential of this strain is not known but the relative pandemic potential is low. Transmissibility of A (H1N1) virus Most epidemiologists consider the transmissibility of a strain to be the most important factor in determining the pandemic potential of a strain. The transmissibility of the virus is measured by the reproduction number (R). This is the average number of cases one case generates during the infectious period. If this number is more than 1, it denotes that the virus is spreading in viable form whereas if it is less than 1, it denotes that the viral activity within a population is subsiding. In a study conducted in 2009 during the early days of Pandemic H1N1/09 in Mexico, scientists used several methods to ascertain the R of A (H1N1) virus (Fraser, Donelly and Cauchemez). By assuming exponential growth and the generation time distribution of A (H1N1) virus to be similar to other strains and using the cumulative number of infections and the date of commencement and the size of the epidemic, the scientists obtained a basic R or R0 to be 1.40 with a range of 1.15 to 1.90. Similarly, when Bayesian coalescent population genetic analysis was used, R0 came out to be 1.22. Using a third method, analysis of the dynamics of the epidemic within defined settings was incorporated into calculations giving an R0 of 1.52. Thus which ever method was used, A (H1N1) virus showed a reproduction number of more than 1 indicating high transmissibility and high potential of causing a pandemic. The transmissibility of a virus is affected by several factors. These factors include the genetic and antigenic make-up of the virus, immunity within a population, containment measures and the use of antiviral medications and vaccines. The genetic and antigenic make-up and shifts of the virus have already been discussed. The other three factors will now be discussed in some detail. Pre-existing immunity within a population is very important in allowing the virus to infect large populations. In a study aimed at finding out whether the general population was immune to the new strain of influenza, the researchers used the Immune Epitope Database and compared the recognition of this circulating strain by B and T cells. It was seen that some T-cell mediated immunity against the A (H1N1) strain is present in adult population and that this immunity is very similar in size to immunity against other strains of influenza (Greenbaum, Kotturi and Kim). This means that the severity and spread of the disease by the new strain is very close to that of earlier strains. Another study suggested that repeated exposure to seasonal influenza strains may be responsible for the low number of affected individuals by H1N1 pandemic who are over 40 years of age (Zheng and Cardona). This is because they have had more exposure to influenza strain. Not only does this explain the relative sparing of older people by A (H1N1) virus but also the general trend of mild symptoms. Containment measures were undertaken in most countries around the world in order to prevent the spread of the virus. These measure included isolation areas of those who were suspected or confirmed cases of swine flu, closure of schools and restrictions on travel. In Australia, anyone returning from North America or Mexico or anyone who was in close contact with a confirmed case of swine flu had to go through initial laboratory testing in order to rule out the possibility of carrying the virus (Grayson and Johnson). European Union also advised European national to avoid travelling to the Americas. Schools in several countries were closed for limited periods during this time and people from all walks of life were instructed to avoid crowds and wear masks. Vaccination weeks were held throughout America in order to muster prophylactic immunity against the new Influenza strain. How far these measures were affective remains a question to date as the virus still spread to most parts of the world and the cost of disturbing everyday lives against the benefits of it was repeatedly questioned. There were allegations against WHO of causing fear and panic instead of bringing calmness and security to the affected nations. Even the method of grading the influenza pandemic came under intense scrutiny (Hayward). The last of these factors is the use of antiviral drugs and vaccines during the pandemic. In several countries, people were treated for mild symptoms of seasonal flu with oseltamivir in suspicion of swine flu. According to a study at Austin Health Center, Australia, 80% of patients received swine flu treatment without having swine flu. Not only was this a burden on public health systems across the world but it had the potential to give rise to a highly resistant strain of A (H1N1) virus. Pandemic H1N1/09 was luckily mild but prophylactic and reckless use of anti virals posed the threat of a disastrous influenza pandemic. A (H1N1) virus was expected to be susceptible to oseltamivir (Thanyada Rungrotmongkola, Kaiyaweta and Sompornpisuta) but by the middle of the pandemic, resistant cases were being seen. Vaccinations were tested for efficacy against the new strain and were said to be as efficacious as 83% (Belshe and Gruber). Compared to other interventions, vaccinations considerably decreased the pandemic potential of A (H1N1) virus. Conclusion The analysis of the studies and their results regarding the Pandemic H1N1/09 has shed light on some very important aspects of this pandemic and has allowed conclusions to be drawn that highlight some important facts about the pandemic potential of a new strain of Influenza A (H1N1) virus. Although most of these studies were conducted either in the early stages of the pandemic or during the pandemic, they render the most valuable information regarding the behavior of the virus during the pandemic. This can help in assessing the possibility of a future influenza pandemic. The pandemic arose during the period of seasonal influenza infections in a small town of Mexico and quickly spread to the southern regions of USA. From there it spread to Europe and Australia. Asia was the last region to be affected. This shows that the virus followed the seasonal variation of flu and although it started in an underdeveloped country with a compromised healthcare system, it went on to hit USA, Europe and Australia in spite of their very efficient healthcare systems. Thus the virus was considerably different from its ancestors yet retained the basic qualities of Influenza A. It also shows that it had a strong link with travel and human-to-human transmission. This trend was also present during the three influenza pandemics earlier in the history. WHO formulated a set of phases which divided the pandemic into 6 phases on the basis of transmissibility and virulence. On 11th June 2009, the influenza pandemic was raised to phase 6 indicating significant human-to-human transmissions. An organism can cause a pandemic when it is introduced into a population without pre-existing immunity to it. The A (H1N1) virus was discovered to be a reassorted form of 1918 virus which had undergone antigenic reassortment with 1918virus, H3N2 virus and rH3N2 virus. Thus this virus was relatively new to the world population and as a consequence, spread quickly. Studies into the genetics of this virus showed that its pathogenicity did not lie in the proteins that had rendered 1981 virus and H3N2 virus highly pathogenic, namely the PB1-F2 and NS1 proteins. Instead the PB2 proteins were suspected to have been responsible for the pathogenicity of A (H1N1) virus. However, this did not render the flu vaccines and medications ineffective as these work on the HA of the virus and this was not changed in A (H1N1) virus. The second factor upon which the pandemic potential of a strain is dependent is the virulence of that strain. The measurement of this factor depends upon the Case Fatality Ratio which could not be determined as the actual number of people affected by this influenza strain will never be known. However, according to WHO, the total number of deaths during the pandemic are 18449. This is a relatively small number in comparison to the expanse of the population and geographical area that was affected by the disease. Scientists concluded that although this strain had a higher virulence than its ancestors, it led to mild symptoms generally. They were unable to find out the virulence factors or virulence markers and attributed this to the ongoing antigenic diversity within the virus. This diversity was a strong indication of the high potential that this virus held of causing a pandemic since it was unpredictable in its antigenic diversity and required very close monitoring. However, the virulence of virus was partly dependent on the HA and was very similar to that of other strains of Influenza A. The third factor to be considered when assessing the pandemic potential is the transmissibility of the virus. This is measured in terms of the reproduction number, R. Multiple methods of calculating R were used and the value was always more than 1 indicating high transmissibility. Evidence of pre-existing immunity to the new viral strain due to exposure to earlier viral strains was provided by several studies which also explained the very few incidences of swine flu in populations aged over 40 years compared to younger age groups. Several measures taken to stop or reduce the transmission were studied. These were implemented in different forms and to different degrees throughout the world and their effectiveness were assessed. These included isolation of patients and close contacts, travel restrictions, laboratory testing of close contacts and travellers, closure of schools, antiviral treatments and vaccinations. Apart from vaccinations, no other intervention was effective. In conclusion, the new strain of Influenza A (H1N1) virus possesses a substantial potential of causing a pandemic and requires a close surveillance in all regions of the world. The use of antiviral medication should be undertaken with caution in order to avoid the rise of a resistant strain and further studies must be initiated aimed at discovering the virulence markers of this strain so that the treatment offered for swine flu is very specific. Works Cited Baigent, Susan and John McCauly. "Influenza type A in humans,mammals and birds:: determinants of virus virulence, host-range and interspecies transmission." Bioessays 2003: 657-671. Belshe, Robert and William Gruber. " Correlates of Immune Protection Induced by Live, Attenuated, Cold-Adapted, Trivalent, Intranasal Influenza Virus Vaccine." The Journal of Infectious Disease (2000): 1133-1137. Dyede, Varough, et al. "Surveillance of Resistance to Adamantanes among Influenza A(H3N2) and A(H1N1) Viruses Isolated Worldwide." 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