Influenza pandemics of 1918 and 2009: a comparative account

110.2217/FVL.13.18 © 2013 Future Medicine Ltd ISSN 1746-0794Future Virol. (2013) 8(4), 1–8

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The 20th century witnessed three influenza pan-demics: the Spanish Flu (1918, H1N1), Asian Flu (1957, H2N2), and the Hong Kong Flu (1968, H3N2). Influenza pandemics are initiated by the introduction and successful adaption of a new virus subtype with a novel hemagglutinin (or novel hemagglutinin [HA] and neuraminidase [NA]) that is immunol ogically distinct from previously circulating strains [1]. The new virus subtype may arise by either of two mechanisms: by the direct transmission of animal influenza strains to humans, as happened in 1918 with the ‘Spanish influenza’ (H1N1); or through reassortment between human and animal influ-enza virus, as occurred in 1957 with the ‘Asian influenza’ (H2N2), and again in 1968 with the ‘Hong Kong influenza’ (H3N2) (Table 1).

The 1918 Spanish flu killed an estimated 50–100 million people worldwide, and has been aptly referred to as ‘the mother of all pandem-ics’ [2]. The pandemic strain of 1918 could not be isolated during the pandemic period, but the molecular secrets behind its high virulence were revealed once the virus was reconstructed using reverse genetics technology on RNA from the lungs of several victims [3].

The influenza pandemic of 1957 was caused by the Asian influenza A (H2N2) strain, and the Hong Kong influenza A (H3N2) strain caused the 1968 pandemic. The two pandemics claimed approximately 500,000–2,000,000 human lives [4]. Both of these reassortant pandemic virus strains emerged in China and included a com-bination of avian and human viral genes [5].

In 1997, 18 cases of avian influenza A H5N1 infection occurred in humans in Hong Kong. It became evident that the avian influenza virus

H5N1 could cross the species barrier and infect humans. Since then, extensive outbreaks of avian H5N1 infections with sporadic human spread have been occurring in various countries. H5N1 influenza virus had previously not been isolated from humans, raising concern over the possi-bility of an upcoming influenza pandemic. The human H5N1 virus was not a reassortant like the 1957 and 1968 pandemic strains; instead, all of the viral genes originated from avian virus [6].

The influenza virus resurrected itself again in March–April 2009, when a novel strain was iso-lated from humans in Mexico and USA, followed by a worldwide spread across 214 countries, caus-ing approximately 500,000–1,000,000 deaths. In August 2010 the WHO declared the end of phase six of this influenza pandemic, and the beginning of the postpandemic period. In the postpandemic period, the H1N1 2009 virus demonstrated the attributes of a seasonal influ-enza virus and may continue to circulate for more years to come [101]. A/California/7/2009 (H1N1) pdm09-like virus has been included in the vaccine strain for the year 2012–2013, indi-cating its continued circulation around the world [102]. The 2009 pandemic strain shares striking similarities with the 1918 pandemic virus, and their in-depth ana lysis may solve many mysteries surrounding the 2009 pandemic (Table 2).

Origin & epidemiologyIt is necessary to look to history in order to understand the genesis of influenza pandemics. The genetic sequencing of the 1918 virus sug-gests that it was an avian influenza virus strain that adapted itself to humans [3]. The phyloge-netic ana lysis of the HA and NA genes support

Influenza pandemics of 1918 and 2009: a comparative account

Madhu Khanna*1, Latika Saxena1, Ankit Gupta1, Binod Kumar1, Roopali Rajput11Department of Respiratory Virology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India 2Department of Respiratory Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India *Author for correspondence: Fax: +91 11 27666549 n [email protected]

The 2009 influenza pandemic A(H1N1)pdm09 of swine origin and the continued circulation of highly pathogenic avian H5N1 strain in humans are stark reminders of the unpredictable nature of the influenza virus. Experiences from the 1918 and the 20th century influenza pandemics helped immensely to prepare a better response for A(H1N1)pdm09. The explosive pattern of the 1918 pandemic makes it a benchmark for pandemic planning and preparedness today. Its similarities with the 2009 pandemic makes it even more intriguing, and it is a great surprise that the two strains, separated by a period of 91 years, share such similar features. This review is an attempt to summarize the literature describing the important features of the 1918 and 2009 pandemics. This may provide a better understanding for the early detection and control of influenza pandemics in the future.

Keywords

n 1918 H1N1 pandemic n 2009 H1N1 pandemic n influenza

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the fact that the precursor virus had not circu-lated in human or swine population in the few decades immediately before the start of the 1918 pandemic [7].

The striking feature of the 1918 pandemic was that it was the first time that both pigs and humans were infected simultaneously with an avian-like influenza virus [2,8]. In contrast with interpandemic seasonal influenza, where the majority of influenza-related deaths occur in the elderly, the pandemic periods witness a marked mortality age shift towards a younger population. The age shift during the 1918 pan-demic was extreme, in which the majority of deaths occurred amongst persons under 45 years of age, sparing people above this age [9]. The most significant pattern in the epidemiology of the 1918 pandemic was the unusual W-shaped mortality pattern peculiarly associated with an overwhelming number of deaths in young adults between 20 and 40 years of age [5]. ‘Antigen recy-cling’ is a phenomenon by which exposure to influenza antigen in childhood results in lifelong protection, and results in mortality sparing in seniors when a similar antigen emerges many years later. This might explain the pandemic age shift to younger age groups, which was also consistent with the recent A(H1N1)pdm09, with a mean age of influenza-related deaths

of approximately 30–42 years compared with approximately 77 years in the interpandemic season. Chowell et al., reported a herald pan-demic wave with elevated mortality in young adults that was similar to the USA and Europe [10]. The mortality rates reflected the fact that even the Mexican seniors ≥65 years of age were not spared, and experienced influenza-related excess mortality that was in contrast to that of the USA and Europe. The ‘first wave’ of the 1918 pandemic arose in the USA in March 1918. However, it is difficult to assign a geographical point of origin due to the simultaneous appear-ance of influenza in March–April 1918 in North America, Europe and Asia. The ‘second wave’ or the main wave occurred in September–Novem-ber 1918. In many places there was a severe third wave of influenza in early 1919 [11]. The pattern of the 1918 pandemic waves was not universal, and data from New York City suggested prepan-demic activity before the spring of 1918, with an impact that was far from mild [12].

After its emergence in North America, the 2009 pandemic influenza virus spread rapidly throughout the world. In contrast with the 1918 H1N1 influenza virus, the 2009 H1N1 strain was generated by reassortment between two well-established swine influenza lineages, and was a highly virulent amalgam of swine, human

Table 1. Pandemics caused by influenza A virus in the past century.

Year Subtype Resulting pandemic Estimated deaths (millions)

1918 H1N1 Devastating 50–100

1957 H2N2 Moderate 1–4

1968 H3N2 Mild 1–4

2009 H1N1 Mild 0.5–1

Table 2. Comparative features of the 1918 and 2009 influenza pandemics.

Basis of comparison 1918 (H1N1) pandemic 2009 (H1N1) pandemic

Isolation of the strain Could not be isolated Isolated soon after detection

Genetic basis De novo genetic adaptation of avian virus into humans

Genetic reassortant of avian, human and swine influenza strains

Pathogenicity Highly pathogenic Moderately pathogenic

Low incidence rates in individuals >65 years

Observed due to first exposure to antigenetically related H1N1 virus

Observed due to first exposure to antigenetically related H1N1 virus

Hemagglutinin structure Tip of hemagglutinin is bald (nonglycosylated)

Tip of hemagglutinin is bald (nonglycosylated)

Antiviral drugs Not available at that time Neuraminidase inhibitors were recommended (within 48 h of illness onset)

Vaccine Not developed Developed within 6 months of detection

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and avian influenza genes (Figure 1) [13]. The NA and M genes were derived from the Eurasian swine genetic lineage. The HA, NP and NS gene segments were derived from the classical swine lineage. The PB1, PB2 and PA gene segments were contributed by the swine triple-reassortant lineage [14]. Compared with past influenza pan-demics, the median reproduction number dur-ing the 2009 pandemic was similar to the 1968 pandemic, or slightly smaller than that of 1918 or 1957 [15]. In a study involving 11 countries, it was observed that in 2009, approximately 75% of the confirmed cases were below 30 years of

age, with a modest peak at the 10–19 age group. Fewer than 3% of the cases were in individuals ≥ age 65. The drop in incidence after age 20 was marked and uniform [16]. The phenomenon known as ‘senior sparing’ was observed in age cohorts born prior to the 1957 pandemic. It is consistent with first exposure to antigenically-related A/H1N1 viruses in childhood, a pat-tern consistent with the ‘antigen recycling’ and ‘original antigenic sin’ hypotheses [17].

The A(H1N1)pdm09 waves varied substan-tially in number and intensity across the globe. Chowell et al. reported the occurrence of a

1990

North American swineH3N2 and H1N2

Avian Human H3N2 Classic swine H1N1 Eurasian swine

Pandemic human H1N1-2009

2000

2009

Figure 1. Reassortment in influenza A virus from 1990 to 2009.

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‘herald’ pandemic wave in the spring of 2009 in Mexico, the USA and the UK, followed by one or more waves during the summer and fall of 2009 [18]. The Southern Hemisphere expe-rienced only a single pandemic wave in 2009. Other countries in Europe also experienced a single main wave in the fall of 2009, followed by a recrudescence of H1N1 activity more than a year later in winter 2010–2011. Their study also supports the effectiveness of early mitigation efforts and cancellation of large public gather-ings, including the closure of schools. Mexico experienced three pandemic waves of A(H1N1)pdm09, associated with higher excess mortality rates than those reported in other countries. A recrudescent wave began in Mexico in December 2011, following a 2-year period of sporadic trans-mission. A substantial change in the age distri-bution of cases and deaths during December 2011 – February 2012 was observed in Mexico compared with A(H1N1)pdm09. In 2011–2012, there was a significantly higher proportion of hospitalization of laboratory-confirmed A/H1N1 individuals older than 60 years. There was also a reduction in the proportion of A/H1N1-positive hospitalizations among school-age children compared with the 2009 pandemic. The age shift observed in the 2011–2012 winter season could be attributed to the emergence of a drift variant A/H1N1 and/or the buildup of immunity among younger patients [17].

Host range & infection of laboratory animals

Study of the 1918 H1N1 virus in several experi-mental systems has confirmed that it does indeed have unique virulence properties that explain its devastating impact on the human population. The virus also displayed an unusual ability to kill chicken embryos, a characteristic typical of avian influenza viruses and not seen in a control human influenza virus [19]. High virulence in these systems correlated with enhanced replica-tion of the 1918 virus in primary human bron-cho-epithelial cells, providing evidence that the 1918 virus has unique capabilities in a human system. In a separate study, the 1918 virus caused severe and fatal disease in experimentally inocu-lated ferrets, characterized by lethargy, anorexia, rhinorrhea, sneezing, severe weight loss and high fever [20]. The 1918 virus also displayed the unusual capacity to cause a lethal disease, char-acterized by potent proinflammatory responses, in nonhuman primates.

The A(H1N1)pdm09 replicates efficiently in nonhuman primates, causing more severe

pathological lesions in the lungs of infected mice, ferrets and nonhuman primates than the seasonal human H1N1 virus, and transmits among ferrets [21].

Clinical manifestationsInfluenza infection is self-limiting in humans, but the virus is notorious for causing substan-tial mortality and morbidity worldwide. Clinical features of influenza virus infection in humans encompass a wide spectrum, from mild rhini-tis and coryza to severe, fulminant infections such as pneumonia and acute respiratory distress syndrome. Although a variety of specimens can be collected for the diagnosis of influenza virus infection, the yield varies. Nasal secretions are considered to be the best specimen for the diag-nosis of influenza virus followed by throat swab, urine and serum [22].

Pandemic and seasonal influenza virus infec-tions share similar signs and symptoms, which make it difficult to differentiate between the diseases caused by the two. The 1918 influenza virus infection was associated with acute onset of chills, frequent epistaxis, myalgia and prostra-tion. The infection had a deleterious and sup-pressive effect on the bone marrow leading to splenomegaly and rendering the host vulnerable to secondary bacterial infections [5]. Extensive organ involvement was an outstanding feature of the 1918 H1N1 pandemic.

In comparison to the 1918 virus infection, the clinical features of the 2009 pandemic were milder. The most common signs and symptoms among A(H1N1)pdm09-positive inpatients were cough, malaise, headache and fever. At the time of presentation, dyspnea, cya-nosis and prostration were significantly associ-ated with the risk of death amongst the virus-positive inpatients [23]. Studies from New York city based on investigation of deaths associated with A(H1N1)pdm09 infection suggests that tracheitis and/or bronchitis was present in all cases, with diffuse alveolar damage associated with viral pneumonia as the primary pathology. Second, influenza viral antigen was distributed predominantly in the tracheobronchial epithe-lium and submucosal glands, and to a lesser extent in bronchiolar epithelium and alveolar epithelial cells and macrophages. Finally, bac-terial pneumonia was observed in 55% of the cases and comorbidities in 91% of adult and adolescent decedents (with obesity in 72%). These findings were strikingly similar to the published studies on autopsies based on the 1918 and 1957 pandemics [24].

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Early in the pandemic, the disease occurred overwhelmingly in children and younger adults, with cough and fever as the most prevalent clinical symptoms of the confirmed cases. The unique features of the A(H1N1)pdm09 infec-tion were the complaints of diarrhea and vom-iting in a significant number of patients [25]. In severe cases, pneumonia and mild fibrosis were observed. At the time of presentation, most patients had multifocal consolidation and the development of pleural effusion [26]. In a recent study based on postmortem findings of nine patients from India, it was observed that viral antigens were localized on the ciliated epithelium of the proximal airway. The virus proliferated in the upper respiratory tract and affected the lower respiratory tract indirectly through the release of inflammatory cytokines. The pathological findings in extrapulmonary organs were attributed to multiorgan dysfunc-tion syndrome rather than a direct viral cyto-pathic effect. There was no evidence of trans-placental transmission of virus from the mother to the fetus. Patients were prone to fungal and viral coinfections and also bacterial infections, depending upon their environment.

Secondary bacterial coinfection was the most frequent complication of influenza during the 1918 and 1957 influenza virus pandemics. The frequency of these bacterial coinfections has decreased in subsequent pandemics, especially the 2009 influenza A (H1N1) pandemic. Bacte-rial pneumonia was observed in 55% of cases, in comparison with 90% of 1918 pandemic autopsies and 75% of 1957 autopsies [27]. The decreased cases of bacterial pneumonia in 2009 influenza A (H1N1) can be attributed to better diagnosis, medical access and the availability of broader antimicrobial treatment [28,29].

In the influenza pandemics of 1957 and 1968, clinical illness was mostly confined to the respi-ratory system, while the infections caused by the 1918 and the human H5N1 strains caused multi-system dysfunction and immune dysregulation. This suggests that highly pathogenic influenza viruses that directly adapt to humans are capa-ble of causing a more severe and inappropriate immune response than reassortant viruses [5].

Serology & antigenic characteristicsHancock et al., have shown the presence of detect-able antibodies against 2009 H1N1 between 8 and 14 days after onset of infection, with more than 85% of the subjects tested having antibody titers of 32 or greater by hemagglutination inhi-bition after 15 days [30]. Initial reports suggested

that seasonal influenza vaccines failed to elicit any cross-reactivity against the 2009 pandemic virus in humans, suggesting considerable anti-genic divergence. However, this observation was later contradicted by studies such as one in Mex-ico involving 60 confirmed cases of A(H1N1)pdm09 influenza virus [31]. This study further indicates that the 2008–2009 trivalent inacti-vated vaccine (A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and (B/Florida/4/2006-like antigen) may provide some protection against A(H1N1)pdm09 virus. Moreover, none of the vaccinated cases of influ-enza A/H1N1 died, indicating that seasonal vac-cination might protect against the most severe forms of the disease. The proportion of patients who died among vaccinated cases was signifi-cantly lower than among unvaccinated cases. In another study from Canada it was observed that prior receipt of 2008–2009 trivalent inacti-vated vaccine was associated with increased risk of medically attended pH1N1 illness during spring–summer 2009. [32]

Interestingly, several of the immunogenic pep-tides derived from the A(H1N1)pdm09 influ-enza virus were representative of the 1918 H1N1 pandemic virus rather than the recent seasonal influenza strains [33]. It has been shown that the A(H1N1)pdm09 monovalent vaccine protects mice from 1918 Spanish influenza virus [34]. In a separate study, immunization with the sea-sonal trivalent influenza vaccine of 2010–2011 protected ferrets from the reconstructed 1918 virus [35]. These observations are suggestive of a certain degree of similarity between the two pandemic strains. The HA genes of the two pan-demic strains are different from those of the sea-sonal viruses in terms of glycosylation sites. All the seasonal strains show the presence of at least two glycosylation sites at the top of their HAs, whereas the two pandemic strains are ‘bald’, lacking these sites. The absence of glycosylation sites at the top of these molecules account for the difference in immune response, as these sugars form a cloud around the HA, masking the abil-ity of the antibody to recognize the right amino acid [36].

The H1 HA molecules have four distinct antigenic sites: Sa, Sb, Ca and Cb [37]. The crystal structure of the hemagglutinin of A/Cal/04/2009 H1N1 virus reveals that the anti-genic structure, especially within the Sa anti-genic site, is extremely similar to that of the 1918 H1N1 virus. 2D1, an antibody from the survivor of the 1918 pandemic that neutralizes both 1918 and 2009 pandemic virus, reveals an

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epitope that is conserved in both the pandemic virus [103].

The HA gene of the 2009 pandemic virus has acquired a proline-to-serine substitution at position 200, which might have resulted in decreased virulence compared with the 1918 pandemic virus.

The NA gene facilitates influenza virus release by the cleavage of the terminal sialic acid resi-dues that are receptors of the viruses HA protein. The NA gene of the 2009 pandemic virus dif-fers by 18.2% from the seasonal H1N1 virus, which possibly rendered the seasonal vaccines ineffective against this novel virus [38].

Antiviral strategiesSince the 1918 influenza pandemic, pharmaceu-tical advances in antiviral therapy have been sig-nificant. The unavailability of antibiotics during the 1918 pandemic and inadequate treatment of bacterial pneumonia accounted for a large number of deaths. Moreover, no vaccines were available against influenza during the 1918 pan-demic. Antiviral drugs play an important role in the control of novel viral strains for which no vaccines are available. The CDC recommends the use of the neuraminidase inhibitor antiviral drugs (oseltamivir and zanamivir) as an impor-tant adjunct in the prevention and treatment of influenza, provided they are administered within 48 h of illness onset [39]. The availability of drugs to control influenza during the 2009 pandemic was extremely helpful, along with the strain-specific vaccine that was developed within 6 months of the first detection of the 2009 pan-demic virus. The ongoing research to discover novel compounds active against the influenza virus serves as a beacon of light for tackling such novel strains [40].

ConclusionThere have been considerable advances in medi-cal technology and scientific knowledge in deal-ing with influenza since the early 1900s. Preven-tion strategies involving annual influenza vacci-nation and a global prevention infrastructure are in place. Still, the influenza virus continues to pose novel challenges by donning new disguises that manage to outwit our immune system. While the planning for the next influenza pan-demic was centered on the possible emergence of a new influenza A subtype of avian origin, the first pandemic of the 21st century was caused by a reassortant swine influenza virus of the same subtype as the circulating human seasonal influenza A. Even though a century separates

the emergence of the two viruses, the HAs of the 1918 pandemic virus and A(H1N1)pdm09 virus have marked similarities. These two pan-demics teach us a valuable lesson: that influenza pandemics are unpredictable in nature and may often deliver surprises.

Extensive globalization and high rates of air travel facilitate the rapid spread of influenza virus, as happened with A(H1N1)pdm09. However, in 1918 when global air travel was not as advanced, the virus was still transmitted rapidly, spread-ing around the world within a few weeks. Even after a century, mysteries surrounding the 1918 pandemic have not been fully solved and new pandemics continue to evolve. These pandemics expose the fact that there are gaps that need to be addressed in influenza surveillance in humans and other animals. A significant fraction of the population is now expected to be protected from A/H1N1 influenza through natural exposure or vaccination. There is also potential for the emer-gence of drift variant of A(H1N1)pdm09 and/or emerging age patterns that are often witnessed during post-pandemic periods. We must there-fore remain vigilant and continue to monitor the epidemiology and health burden of the A/H1N1 influenza virus. Animal health workers and human health workers should work in col-laboration to achieve heightened surveillance in swine and other animals. A multinational comparison of the epidemiology of pandemic and postpandemic waves would offer insights on the long-term transmission dynamics of the pandemic viruses, thus helping to formulate con-trol strategies.

There is an urgent need to develop methods that reduce the time gap between the detection of a virus and wide availability of the vaccine. The current shortcomings lies in our depend-ence on the development of egg-based vaccines, which is inconsistent and slow. Furthermore, large-scale sequencing, bioinformatics ana lysis and working with recombinant viruses to predict the emergence of new pandemics is the need of the hour.

Future perspectiveThe influenza pandemics of 1918 and 2009 are a grim reminder of the importance of continuing the fight against influenza. We must examine these pandemics for future implications in pan-demic risk assessment and preparedness. Lessons learnt from the 1918 and 2009 influenza pan-demics will help in the early detection, preven-tion and surveillance of influenza virus that will prepare us for future pandemic situations.

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ReferencesPapers of special note have been highlighted as:n of interest

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Executive summary

The 1918 (H1N1) pandemic�n Killed an estimated 50–100 million people. �n Although the first wave originated in USA, it is still difficult to assign a geographical point of origin due to its simultaneous appearance

in other parts of the world.�n Exhibited a W-shaped mortality pattern associated with an overwhelming number of deaths in young adults.

The 2009 (H1N1) pandemic�n First isolated from humans in Mexico and USA.�n Caused approximately 0.5–1 million deaths worldwide.�n Shared striking similarities with the 1918 pandemic virus.

Comparative features of the 1918 and 2009 influenza pandemics�n Age shift during the 1918 pandemic was extreme, in which the majority of deaths occurred among individuals under 45 years of age,

sparing people above this age.�n During the 2009 influenza pandemic approximately 75% of confirmed cases were below 30 years of age and fewer than 3% of the

cases were in individuals ≥ age 65.�n Extensive organ involvement was an outstanding feature of the 1918 H1N1 pandemic. In comparison with the 1918 virus infection, the

clinical features of the 2009 pandemic were milder.�n The crystal structure of the HA of both the viruses is similar, especially within the Sa antigenic site.�n Compared with seasonal influenza outbreaks, the overall impact of the 2009 H1N1 pandemic was lower in adults ≥65 years of age. This

is possibly due to the presence of protective cross-reactive antibodies developed through childhood exposure to the 1918 pandemic virus, with which it shares antigenic similarity.

Conclusion�n These two pandemics teach us a lesson that influenza pandemics are unpredictable and are prone to delivering surprises.�n There are gaps that need to be addressed in influenza surveillance in humans and other animals.�n We must remain vigilant and continue to monitor the epidemiology and health burden of the A/H1N1 influenza virus.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials dis-cussed in the manuscript. This includes employ-ment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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