Travel Medicine and Infectious Disease (2015) 13, 217e222
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
REVIEW
Insights from unusual aspects of the 1918 influenza pandemic G. Dennis Shanks a,b,* a b
Australian Army Malaria Institute, Enoggera, QLD 4051, Australia University of Queensland, School of Population Health, Brisbane, QLD 4006, Australia
Received 15 April 2015; accepted 5 May 2015
Available online 14 May 2015
KEYWORDS 1918 influenza pandemic; Epidemiology; Mortality; Pathogenesis
Summary The 1918 influenza pandemic was the most lethal single event in modern history. Besides its mortality the 1918 pandemic was unusual for several reasons. It preferentially killed young adults from 20 to 40 y with a peak mortality at age 28 y. Mortality was highly variable with death rates varying by at least 10 fold within similar groups of citizens, soldiers, cities and islands. Secondary bacterial pneumonia following influenza was the overwhelming cause of death and not viral pneumonitis or acute lung injury. Clinical expressions of the 1918 pandemic were unusual with bleeding into the respiratory tree including epistaxis and dark blue cyanotic skin. The 1918 influenza virus apparently ceased circulation in the human population in the early 1920s but continued to evolve in pigs. Immunizations using viruses from 1918 and 2009 can cross-protect laboratory animals even though the human mortality outcomes were very different between the first pandemics of the 20th and 21st centuries. Unusual aspects of historical epidemics may help to reconstruct what actually occurred in 1918 and thus better prepare for the next pandemic. Crown Copyright ª 2015 Published by Elsevier Ltd. All rights reserved.
1. Introduction The 1918 influenza pandemic was the most lethal single event in recent history killing tens of millions globally, yet it is also one of the least understood major modern infectious disease outbreaks [1e4]. Several unusual or unique
* Australian Army Malaria Institute, Enoggera, QLD 4051, Australia. Tel.: þ61 7 3332 4931; fax: þ61 7 3332 4800. E-mail address: [email protected].
characteristics mark the 1918 influenza pandemic as being different from other influenza pandemics specifically and infectious disease epidemics generally [5]. The influenza virus causing the 1918 pandemic preferentially killed young adults, the healthiest segment of the population. It was also highly variable in its mortality outcome with rates varying >10 fold in apparently identical groups often those located in the same area at the same time. The final lethal event for the vast majority of patients in 1918 was a secondary bacterial pneumonia which is different from the viral pneumonitis and acute lung injury more typically seen
http://dx.doi.org/10.1016/j.tmaid.2015.05.001 1477-8939/Crown Copyright ª 2015 Published by Elsevier Ltd. All rights reserved.
218 in current avian influenza infections [6]. Clinically the 1918 influenza pandemic was unusual in the number of bleeding phenomenon observed including frequent epistaxis as well as a remarkably blue cyanotic skin labeled “heliotrope cyanosis” at the time. Even in the era of modern transportation it would be difficult for an influenza virus to show peak activity simultaneously on multiple continents much less when being transported in slow troopships as in 1918 [7]. For unclear reasons the lethal strain of virus disappeared in the early 1920s apparently being maintained in swine and subsequently it contributed genetic material to the virus of the 2009 pandemic [3]. These unusual aspects of the 1918 influenza pandemic beg the question of whether it was a unique event shaped by epidemiological events that will not reoccur or if it holds important unappreciated precedents for future influenza pandemics. This review will examine the extensive historical epidemiology data available as well as the admittedly sparse laboratory evidence from a time which predated the discovery of the viral cause of influenza in an attempt to answer the question of the likelihood of an event similar to the 1918 influenza pandemic reoccurring.
2. Young adult mortality Despite most influenza infections in 1918 resulting in uncomplicated respiratory disease, young adults from 20 to 40 y died at much higher than expected rates [5]. This socalled W mortality curve where young adults died as well as the very young and very old was observed with some variation world-wide. That infants would be unable to resist a new virus is not as surprising as was the observation that many older adults survived influenza in 1918 whereas the elderly make up most modern mortality. As an example, despite the many thousands of First World War soldiers who died of influenza, no generals or admirals died unless they were particularly young for their rank due to rapid promotion [8]. More than just a band between 20 and 40 y, mortality specifically peaked in those 28 y of age in most populations where the data could be examined by single years including Canada, USA, England and New Zealand [9e11]. This means the 1890 birth cohort was particularly vulnerable to a worse outcome when infected with influenza in 1918 than those born only a few years earlier or later. Since the previous influenza pandemic began in 1890, it would appear that early life exposure to what was probably an H3N8 virus in 1890 enhanced mortality when infected by an H1N1 virus in 1918 [12]. Early life influenza infection is known to partially determine future immune reactions whereby the greatest serological reaction subsequently is still against the initial virus in a manner termed antigenic seniority or “original antigenic sin” [12]. A swine influenza model where killed virus immunization was followed by heterologous virus infection has been shown to cause a hemorrhagic pneumonitis not seen when using homologous viruses for immunization and subsequent challenge [13]. The mechanism of this enhanced disease during swine influenza is due to antibody-enhanced infection whereby non-neutralizing antibodies actually increase the virus’s ability to infect respiratory epithelial cells. Epidemiological studies in three
G.D. Shanks separate military populations suggest that a similar enhancement of infection was caused by previous influenza-like illness did occur in some closely followed groups in 1918 [14]. In the absence of any clinical samples from 1918 and very few remaining survivors whose first influenza infection occurred in 1918, it is unlikely one will ever be able to prove the relationship between the 1890 and 1918 pandemics, but there is sufficient data to recognize that not all influenza immunity is advantageous to the host. Further suggestions along these lines were found when Canadian seasonal influenza immunization increased illness during the 2009 influenza pandemic [15]. The sequence and timing of influenza infections partially determine subsequent disease outcomes.
3. Highly variable mortality Just as early life influenza infection caused variation in mortality risk in 1918, entire populations appeared to have differing mortality risks despite being infected by the identical virus often in the same geographic area. In New Zealand where the Polynesian Maori population died at four times the rate of British immigrant population, this ethnically determined mortality difference was observed to decease in Maori though successive influenza pandemics [16,17]. Five percent of the Chamorro people died when the US Navy brought influenza to Guam; in spite of simultaneous high infection rates in the US sailors on Guam, only one died. Pacific islands influenza-related mortality varied by 50 fold with the most lethal epidemics occurring on the most isolated islands [18e20]. The infantry battalions with the highest and lowest mortality rates in the Australian Army fighting in Europe in 1918 were co-located in the same brigade rotating through geographic areas together [8]. Entire US cities differed by 10 fold in their influenza-related mortality with no apparent association with any particular geography despite an apparent relationship to past pneumonia rates [21,22]. Other examples could be cited but wherever accurate mortality figures could be generated, groups that would seem to have identical mortality risks actually died with at least a 10 fold difference between lowest and highest units. In 1918 this degree of mortality difference was not due to any medical or social interventions. Host factors were very important in determining the lethality of the 1918 influenza virus even if the exact mechanisms involved remain unknown.
4. Bacterial pneumonia following influenza Influenza infects the cells of the respiratory epithelium causing an acute tracheo-bronchitis which may extend into the lung parenchyma to cause viral pneumonitis [23]. Destruction of the respiratory epithelium blocks normal resistance pathways allowing the entry of bacteria colonizing other parts of the respiratory tree to initiate bacterial pneumonia [24]. Secondary bacterial pneumonia killed approximately one in three patients in the preantibiotic era. The reason influenza in 1918 was so lethal was due to the increased proportion of persons with influenza who subsequently developed secondary bacterial pneumonia and not a difference in case fatality rates in
1918 Influenza Pandemic
219
those with bacterial pneumonia [25,26]. Influenza infection rates were not unusually high and few persons died primarily of pulmonary failure [5]. The key to the great mortality that occurred during the 1918 influenza pandemic is in determining why many more individuals with apparently ordinary influenza went on to develop bacterial pneumonia. Although our medical predecessors in 1918 did not understand viruses, bacteriology was well developed and used extensively during the pandemic [27]. It can be confidently stated that the vast majority of bacterial pneumonias in 1918 were due to familiar pathogens such as Streptococcus pyogenes, Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae [28e32]. In the large military recruit training camps of the US Army, usually one of these common pyogenic pathogens predominated although the species varied among the different camps [24]. Furthermore, different ethnic populations in the same camp could show a difference in the predominant bacterial pathogen found at autopsy [33]. Isolation of influenza patients to minimize their exposure to other persons thus preventing newly acquired bacteria colonizing their upper respiratory tree was shown to decrease mortality rates [25,26,34]. The lack of effective medical interventions in 1918 meant it was often better to be managed at home by one’s family than to be admitted to a chaotic emergency hospital ward full of many other sick influenza patients as hospitals increased exposure to many respiratory pathogens besides influenza virus. Certainly secondary bacterial pneumonia is observed following influenza infection today but even accounting for the near universal use of antibiotics in current intensive care units, bacterial pneumonia was remarkably common in 1918 for as yet unclear reasons [6,35,36].
5. Clinical manifestations In most ways other than its extreme lethality, the 1918 influenza pandemic was clinically the same as influenza before and since [25,37]. There were, however, two clinical aspects that were widely noticed by the medical officers that have been largely restricted to the 1918 pandemic; bleeding phenomenon especially epistaxis and a very distinctive form of cyanosis [38,39]. Epistaxis or nose bleeding was noted in >10% of some military groups with influenza [38]. It was often severe requiring packing of the nose in order to stop the bright red blood coming from the nostrils. This is atypical for ordinary influenza both in frequency and type of bleeding [34,40]. Further down the respiratory tree, pulmonary hemorrhage was commonly seen on histological examination of pathology specimens but frank hemoptysis was rare [23,25,26]. The 1918 influenza virus was extra-ordinarily destructive to the respiratory epithelium throughout with cellular necrosis being commonly observed microscopically [6,23]. Although some additional bleeding phenomenon were reported such as menometrorrhagia in women, other bleeding diatheses were only rarely seen [28]. It is most likely that both the increased bacterial pneumonia rate and epistaxis are explained by the 1918 virus having an increased pathogenic effect specifically in the destruction of the respiratory epithelium [6,23]. Through cellular necrosis the normal
Figs. 1e3 Different stages of skin coloration as seen during the 1918 influenza pandemic characterized as “heliotrope” or deep blue cyanosis. Reproduced with permission from the Lancet archives.
220 ciliary movement of mucus and maintenance of blood vessel integrity were compromised leading to pneumonia and bleeding. The dark blue cyanosis seen in conscious influenza patients was so remarkably different from what had been seen before 1918 that the British Army Medical Corps brought in an artist from the Royal Academy to graphically capture the distinctive color which was described as “heliotrope cyanosis” after a deep blue flower [41] (Figs. 1e3). This was regarded as a very poor prognostic sign with 95% of soldiers showing such cyanosis going on to die usually within a single day [26,34]. The fact that these patients were conscious to nearly the point of death seemed inconsistent with the low oxygen saturation that must have existed to cause such deep cyanosis. The most likely explanation would seem to be that the entire lung was involved in a process that destroyed the epithelium and filled the alveoli with fluid [23]. Ordinary pneumonia usually only involved a few lobes of the lung allowing shunting of blood and thus some oxygenation to proceed through the unaffected parts. “Heliotrope cyanosis” was likely a marker of the extreme pathogenicity of the virus and the resulting cellular necrosis.
6. Appearance and rapid disappearance Despite many hypotheses, the origin of the 1918 influenza virus remains unknown. Genomic information generated from reconstructed nucleic acid sequences from archived pathology specimens seems to indicate that a H1N1 virus had been circulating for some time in a mammalian host prior to 1918 but this interpretation depends on the assumptions made in the models constructed from incomplete data [42,43]. In most parts of the world, an early (range March to June) 1918 pandemic wave was observed causing higher rates of illness but much lower mortality rates than what was seen in the lethal wave starting from August 1918. For example, in the French Army of approximately 4 million men 28,000 died in the late 1918 wave [44]. Some observers think that these waves were caused by two different viruses thus postulating two separate but interrelated influenza pandemics in a single year [45]. In the Australian Army, infection in the early wave made no difference in one’s illness rate in late 1918 although mortality was more than halved late in 1918 if one had a symptomatic influenza-like illness in early 1918 [8]. The most likely explanation would seem to be that at least two distinct but related H1N1 influenza viruses were circulating in 1918. The 1918 influenza virus suddenly appeared in its lethal form in late 1918 with near simultaneous peak mortality rates occurring in some cities in America, Europe, Africa and Asia [46]. Although there is good epidemiological evidence from Europe and genomic information from the USA to indicate that the lethal form of the virus was circulating months prior to its recognition in late 1918, there is no good explanation for how such a virus could suddenly and nearly simultaneously increase its lethality in multiple places across the globe [47,48]. Perhaps the “purulent bronchitis” epidemics observed in First World War soldiers from 1914 to 17 were actually the beginnings of the 1918 pandemic virus
G.D. Shanks indicating that the virus had years to spread globally through the massive movement of people associated with the war [41,49e52]. Just as it is uncertain where the 1918 influenza virus came from, its rapid disappearance is also difficult to explain. The distinctive W mortality pattern of the 1918 virus disappeared early in the 1920s although influenza viruses with less mortality continued to circulate [47]. Recent genomic analyses based on all H1N1 viruses available indicate that what became seasonal influenza in the 1920s was quite different from the pandemic virus of 1918 [43]. The pandemic virus left the human population but carried on as a previously unremarked swine infection. It changed little over time as most pigs only live long enough to experience a single influenza infection which creates little in the way of evolutionary pressure. When the 2009 pandemic arrived, part of its genetic information came from the 1918 influenza virus as maintained in swine [53]. The 2009 viral hemagglutinin is similar enough to that of 1918 to allow cross-protection in laboratory animals when immunized with the other surface protein [54]. Internal viral antigens such as the nucleoprotein also were conserved from 1918 to the 2009 pandemic virus [55]. Despite these antigenic and genomic similarities, the 1918 pandemic is the most lethal influenza virus ever recorded whereas the 2009 pandemic caused the least mortality.
7. Conclusion For several reasons, the 1918 influenza pandemic was an exception [56]. Besides its great lethality there were associated findings that were linked to increased pathogenicity such as epistaxis and deep cyanosis as well as other anomalies that have no obvious explanation such its highly variable mortality in seemingly identical groups. The 1918 enigma, however, is encapsulated in the young adult mortality peak; adequately explain why young adults preferentially died and one would be much closer to understanding its genesis and importance to future pandemics. There have been several hypothesis put forward. The most important aspect seems to be the 1918 pandemic’s relationship to the 1890 pandemic as there is no other way to explain a mortality peak at 28 y [5,9,10]. Exposure in infancy to infectious agents has different immunological implications to infections occurring later in life. The 28 y separation in time argues for long-lasting immune cells such as resident memory CD8þ lymphocytes being an important factor [57]. The inter-connections between the innate and acquired immune systems are still being defined so perhaps a more detailed mechanistic hypothesis may be possible in the future. Regardless of future hypotheses, it is clear that host factors played a large role in determining mortality rates. Persons who had few previous respiratory infections such as soldiers from rural areas died at higher rates in military recruit camps compared to their urban counter-parts [58]. Geographic isolation seemed to determine the level of mortality on Pacific Islands when the 1918 influenza virus arrived. On islands such as Guam, Saipan and Nauru, immigrants with low mortality rates lived next to local populations with high mortality rates strongly suggesting that
1918 Influenza Pandemic previous infection history was the important factor and not some unknown genetic trait. Will the 1918 influenza pandemic with its extraordinary mortality reoccur? Our inability to explain the 1918 pandemic nearly a century later should give all of us reason to be concerned about the limitations of predicting the future. Some would say that the 1918 influenza virus has already returned in the form of the 2009 pandemic. Certainly there are several antigenic and genomic similarities in these two H1N1 viruses. This still does not address the main concern, however, given the great mortality difference between the two pandemics. In spite of being unable to weave all the described attributes of the 1918 pandemic into a single mechanistic hypothesis, it is reasonable to be reassured by the historical differences. These suggest that the lethality of the 1918 influenza pandemic was specific to its timing and geography within certain populations. Nearly a century later, the world is a much different place epidemiologically especially given the increased variety and speed of pathogen circulation. Could influenza cause major new mortality concerns? Based on the very high mortality rates currently seen with H5 and H7 avian influenza, the possibility must be considered [2]. Given the few practical boundaries constraining avian influenza and its inability over the last few decades to cause sustained infection between humans, the risk appears low but the consequences of such a very rare event remain very high. Continued disease surveillance in humans and animals with an on-going annual influenza immunization program are the minimum actions required to maintain readiness against a future influenza pandemic.
Contributors GDS is responsible for the review having entirely written the manuscript.
Conflicts of interest The author claims no conflict of interest.
Funding The author did not receive any specific funding for writing this review.
Disclaimer The opinions expressed are those of the author and do not necessarily reflect those of the Australian Defence Force or the U.S Department of Defense.
Acknowledgments The author thanks the many unnamed colleagues, medical librarians, and archivists who have unselfishly provided data and ideas for this essay.
221
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222 [20] Shanks GD, Waller M, Mackenzie A, Brundage JF. Determinants of mortality in naval units during the 1918e19 influenza pandemic. Lancet Infect Dis 2011;11:793e9. [21] Frost WH. The epidemiology of influenza. Public Health Rep 1919;34:1823e37. [22] Acuna-Soto R, Viboud C, Chowell G. Influenza and pneumonia mortality in 66 large cities in the United States in years surrounding the 1918 pandemic. PloS One 2011;6:e23467. [23] Taubenberger JK, Morens DM. The pathology of influenza virus infections. Ann Rev Path 2008;3:499. [24] Brundage JF. Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness. Lancet Infect Dis 2006;6:303e12. [25] Vaughan VC, Palmer GT. Communicable disease in the United States Army during the summer and autumn of 1918. J Lab Clin Med 1919;4:647e86. [26] Macpherson WG, Herringham W, Elliott T, Balfour A. History of the Great War based on official documents. Medical services. Diseases of the war, Vol. 1; 1922. [27] Gibson HG, Bowman FB, Connor JI. The etiology of influenza: a filtrable virus as the cause, with some notes on the culture of the virus by Noguchi’s Method. BMJ 1919;1:331. [28] Brem WV, Bolling GE, Casper EJ. Pandemic influenza and secondary pneumonia at camp Fremont, Calif. JAMA 1918;71: 2138e44. [29] Cole CEC. Preliminary report on the influenza epidemic at Bramshott in September-October, 1918. BMJ 1918;2:566. [30] Friedlander A, McCord CP, Sladen FJ, Wheeler GW. The epidemic of influenza at Camp Sherman, Ohio. JAMA 1918; 71:1652e6. [31] Hall JN, Stone MC, Simpson JC. The epidemic of pneumonia following influenza at Camp Logan, Texas: preliminary report. JAMA 1918;71:1986e7. [32] Synnott MJ, Clark E. The influenza epidemic at Camp Dix, NJ. JAMA 1918;71:1816e21. [33] Chickering HT, Park JH. Staphylococcus aureus pneumonia. JAMA 1919;72:617e26. [34] MacNeal WJ. Inflammatory diseases of the respiratory tract. In: Ireland MW, editor. War department during the World War. Washington DC: United States War Department; 1919. [35] Brundage JF, Shanks GD. Deaths from bacterial pneumonia during 1918e19 influenza pandemic. Emerg Infect Dis 2008; 14:1193. [36] Oswald NC, Shooter R, Curwen M. Pneumonia complicating Asian influenza. BMJ 1958;2:1305. [37] Duque V, Vaz J, Mota V, Morais C, Da Cunha S, Melic ¸oSilvestre A. Clinical manifestations of pandemic (H1N1) 2009 in the ambulatory setting. J Infect Dev Ctries 2011;5:658e63. [38] MRC. Studies of influenza in hospitals of the British armies in France 1918. Special Report series no 36. London: HMSO; 1919. p. 6e17. [39] Muir R, Wilson GH. Observations on influenza and its complications. BMJ 1919;1:3. [40] MacNeal WJ. The influenza epidemic of 1918 in the American expeditionary forces in France and England. Arch Intern Med 1919;23:657e88. [41] Abrahams A, Hallows N, French H. Influenzo-pneumococcal and influenzo-streptococcal septicaemia: epidemic influenzal pneumonia of highly fatal type and its relation to purulent bronchitis. Lancet 1919;193:1e11.
G.D. Shanks [42] Smith G, Bahl J, Vijaykrisna D, Zhang J, Poon LL, Chen H, et al. Dating the emergence of pandemic influenza viruses. Proc Natl Acad Sci U S A 2009;106:11709e12. [43] Worobey M, Han GZ, Rambaut A. Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus. Proc Natl Acad Sci U S A 2014;111:8107e12. [44] Delater D. La grippe dans la Nation Armee de 1918. Rev d’hygiene 1923;45:408e26. [45] Shanks GD, Milinovich G, Waller M, Clements A. Opinion: spatiotemporal investigation of the 1918 influenza pandemic in military populations indicates two different viruses. Epidemiol Infect Nov 2014 [Epub ahead of print]. [46] Jordan EO. Epidemic influenza: a survey. Chicago: American Medical Association; 1923. [47] Saglanmak N, Andreasen V, Simonsen L, Molbak K, Miller MA, Viboud C. Gradual changes in the age distribution of excess deaths in the years following the 1918 influenza pandemic in Copenhagen: using epidemiological evidence to detect antigenic drift. Vaccine 2011;29(Suppl. 2):B42e8. [48] Sheng Z-M, Chertow DS, Ambroggio X, McCall S, Przygodzki RM, Cunningham RE, et al. Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak. Proc Natl Acad Sci U S A 2011;108:16416e21. [49] Finley F. A letter from No. 1 general hospital, CEF. Can Med Assoc J 1915;5:550. [50] Abrahams A, Hallows NH, Eyre JWH, French H. Purulent bronchitis: its influenzal and pneumococcal bacteriology. Lancet 1917;190:377e82. [51] Eyre JWH, Lowe EC. Report upon the autumn influenza epidemic (1918) as it affected the NZEF in the United Kingdom. Lancet 1919;193:553e60. [52] Oxford JS, Lambkin R, Sefton A, Daniels R, Elliot A, Brown R, et al. A hypothesis: the conjunction of soldiers, gas, pigs, ducks, geese and horses in Northern France during the Great War provided the conditions for the emergence of the “Spanish” influenza pandemic of 1918e1919. Vaccine 2005; 23:940e5. [53] Smith GJ, Vijaykrishna D, Bahl J, et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 2009;459:1122e5. [54] Pearce MB, Belser JA, Gustin KM, Pappas C, Houser KV, Sun X, et al. Seasonal trivalent inactivated influenza vaccine protects against 1918 Spanish influenza virus infection in ferrets. J Virol 2012;86:7118e25. [55] Gras S, Kedzierski L, Valkenburg SA, Laurie K, Liu YC, Denholm JT, et al. Cross-reactive CD8þ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses. Proc Natl Acad Sci U S A 2010;107: 12599e604. [56] Morens DM, Taubenberger JK. 1918 influenza, a puzzle with missing pieces. Emerg Infect Dis 2012;18:332e5. [57] McAuley J, Kedzierska K, Brown L, Shanks GD. Host immunological factors enhancing mortality of young adults during the 1918 influenza pandemic. Front Immunol 2015 [in preparation]. [58] Paynter S, Ware RS, Shanks GD. Host and environmental factors reducing mortality during the 1918-1919 influenza pandemic. Epidemiol Infect 2011;139:1425e30.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
REVIEW
Insights from unusual aspects of the 1918 influenza pandemic G. Dennis Shanks a,b,* a b
Australian Army Malaria Institute, Enoggera, QLD 4051, Australia University of Queensland, School of Population Health, Brisbane, QLD 4006, Australia
Received 15 April 2015; accepted 5 May 2015
Available online 14 May 2015
KEYWORDS 1918 influenza pandemic; Epidemiology; Mortality; Pathogenesis
Summary The 1918 influenza pandemic was the most lethal single event in modern history. Besides its mortality the 1918 pandemic was unusual for several reasons. It preferentially killed young adults from 20 to 40 y with a peak mortality at age 28 y. Mortality was highly variable with death rates varying by at least 10 fold within similar groups of citizens, soldiers, cities and islands. Secondary bacterial pneumonia following influenza was the overwhelming cause of death and not viral pneumonitis or acute lung injury. Clinical expressions of the 1918 pandemic were unusual with bleeding into the respiratory tree including epistaxis and dark blue cyanotic skin. The 1918 influenza virus apparently ceased circulation in the human population in the early 1920s but continued to evolve in pigs. Immunizations using viruses from 1918 and 2009 can cross-protect laboratory animals even though the human mortality outcomes were very different between the first pandemics of the 20th and 21st centuries. Unusual aspects of historical epidemics may help to reconstruct what actually occurred in 1918 and thus better prepare for the next pandemic. Crown Copyright ª 2015 Published by Elsevier Ltd. All rights reserved.
1. Introduction The 1918 influenza pandemic was the most lethal single event in recent history killing tens of millions globally, yet it is also one of the least understood major modern infectious disease outbreaks [1e4]. Several unusual or unique
* Australian Army Malaria Institute, Enoggera, QLD 4051, Australia. Tel.: þ61 7 3332 4931; fax: þ61 7 3332 4800. E-mail address: [email protected].
characteristics mark the 1918 influenza pandemic as being different from other influenza pandemics specifically and infectious disease epidemics generally [5]. The influenza virus causing the 1918 pandemic preferentially killed young adults, the healthiest segment of the population. It was also highly variable in its mortality outcome with rates varying >10 fold in apparently identical groups often those located in the same area at the same time. The final lethal event for the vast majority of patients in 1918 was a secondary bacterial pneumonia which is different from the viral pneumonitis and acute lung injury more typically seen
http://dx.doi.org/10.1016/j.tmaid.2015.05.001 1477-8939/Crown Copyright ª 2015 Published by Elsevier Ltd. All rights reserved.
218 in current avian influenza infections [6]. Clinically the 1918 influenza pandemic was unusual in the number of bleeding phenomenon observed including frequent epistaxis as well as a remarkably blue cyanotic skin labeled “heliotrope cyanosis” at the time. Even in the era of modern transportation it would be difficult for an influenza virus to show peak activity simultaneously on multiple continents much less when being transported in slow troopships as in 1918 [7]. For unclear reasons the lethal strain of virus disappeared in the early 1920s apparently being maintained in swine and subsequently it contributed genetic material to the virus of the 2009 pandemic [3]. These unusual aspects of the 1918 influenza pandemic beg the question of whether it was a unique event shaped by epidemiological events that will not reoccur or if it holds important unappreciated precedents for future influenza pandemics. This review will examine the extensive historical epidemiology data available as well as the admittedly sparse laboratory evidence from a time which predated the discovery of the viral cause of influenza in an attempt to answer the question of the likelihood of an event similar to the 1918 influenza pandemic reoccurring.
2. Young adult mortality Despite most influenza infections in 1918 resulting in uncomplicated respiratory disease, young adults from 20 to 40 y died at much higher than expected rates [5]. This socalled W mortality curve where young adults died as well as the very young and very old was observed with some variation world-wide. That infants would be unable to resist a new virus is not as surprising as was the observation that many older adults survived influenza in 1918 whereas the elderly make up most modern mortality. As an example, despite the many thousands of First World War soldiers who died of influenza, no generals or admirals died unless they were particularly young for their rank due to rapid promotion [8]. More than just a band between 20 and 40 y, mortality specifically peaked in those 28 y of age in most populations where the data could be examined by single years including Canada, USA, England and New Zealand [9e11]. This means the 1890 birth cohort was particularly vulnerable to a worse outcome when infected with influenza in 1918 than those born only a few years earlier or later. Since the previous influenza pandemic began in 1890, it would appear that early life exposure to what was probably an H3N8 virus in 1890 enhanced mortality when infected by an H1N1 virus in 1918 [12]. Early life influenza infection is known to partially determine future immune reactions whereby the greatest serological reaction subsequently is still against the initial virus in a manner termed antigenic seniority or “original antigenic sin” [12]. A swine influenza model where killed virus immunization was followed by heterologous virus infection has been shown to cause a hemorrhagic pneumonitis not seen when using homologous viruses for immunization and subsequent challenge [13]. The mechanism of this enhanced disease during swine influenza is due to antibody-enhanced infection whereby non-neutralizing antibodies actually increase the virus’s ability to infect respiratory epithelial cells. Epidemiological studies in three
G.D. Shanks separate military populations suggest that a similar enhancement of infection was caused by previous influenza-like illness did occur in some closely followed groups in 1918 [14]. In the absence of any clinical samples from 1918 and very few remaining survivors whose first influenza infection occurred in 1918, it is unlikely one will ever be able to prove the relationship between the 1890 and 1918 pandemics, but there is sufficient data to recognize that not all influenza immunity is advantageous to the host. Further suggestions along these lines were found when Canadian seasonal influenza immunization increased illness during the 2009 influenza pandemic [15]. The sequence and timing of influenza infections partially determine subsequent disease outcomes.
3. Highly variable mortality Just as early life influenza infection caused variation in mortality risk in 1918, entire populations appeared to have differing mortality risks despite being infected by the identical virus often in the same geographic area. In New Zealand where the Polynesian Maori population died at four times the rate of British immigrant population, this ethnically determined mortality difference was observed to decease in Maori though successive influenza pandemics [16,17]. Five percent of the Chamorro people died when the US Navy brought influenza to Guam; in spite of simultaneous high infection rates in the US sailors on Guam, only one died. Pacific islands influenza-related mortality varied by 50 fold with the most lethal epidemics occurring on the most isolated islands [18e20]. The infantry battalions with the highest and lowest mortality rates in the Australian Army fighting in Europe in 1918 were co-located in the same brigade rotating through geographic areas together [8]. Entire US cities differed by 10 fold in their influenza-related mortality with no apparent association with any particular geography despite an apparent relationship to past pneumonia rates [21,22]. Other examples could be cited but wherever accurate mortality figures could be generated, groups that would seem to have identical mortality risks actually died with at least a 10 fold difference between lowest and highest units. In 1918 this degree of mortality difference was not due to any medical or social interventions. Host factors were very important in determining the lethality of the 1918 influenza virus even if the exact mechanisms involved remain unknown.
4. Bacterial pneumonia following influenza Influenza infects the cells of the respiratory epithelium causing an acute tracheo-bronchitis which may extend into the lung parenchyma to cause viral pneumonitis [23]. Destruction of the respiratory epithelium blocks normal resistance pathways allowing the entry of bacteria colonizing other parts of the respiratory tree to initiate bacterial pneumonia [24]. Secondary bacterial pneumonia killed approximately one in three patients in the preantibiotic era. The reason influenza in 1918 was so lethal was due to the increased proportion of persons with influenza who subsequently developed secondary bacterial pneumonia and not a difference in case fatality rates in
1918 Influenza Pandemic
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those with bacterial pneumonia [25,26]. Influenza infection rates were not unusually high and few persons died primarily of pulmonary failure [5]. The key to the great mortality that occurred during the 1918 influenza pandemic is in determining why many more individuals with apparently ordinary influenza went on to develop bacterial pneumonia. Although our medical predecessors in 1918 did not understand viruses, bacteriology was well developed and used extensively during the pandemic [27]. It can be confidently stated that the vast majority of bacterial pneumonias in 1918 were due to familiar pathogens such as Streptococcus pyogenes, Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae [28e32]. In the large military recruit training camps of the US Army, usually one of these common pyogenic pathogens predominated although the species varied among the different camps [24]. Furthermore, different ethnic populations in the same camp could show a difference in the predominant bacterial pathogen found at autopsy [33]. Isolation of influenza patients to minimize their exposure to other persons thus preventing newly acquired bacteria colonizing their upper respiratory tree was shown to decrease mortality rates [25,26,34]. The lack of effective medical interventions in 1918 meant it was often better to be managed at home by one’s family than to be admitted to a chaotic emergency hospital ward full of many other sick influenza patients as hospitals increased exposure to many respiratory pathogens besides influenza virus. Certainly secondary bacterial pneumonia is observed following influenza infection today but even accounting for the near universal use of antibiotics in current intensive care units, bacterial pneumonia was remarkably common in 1918 for as yet unclear reasons [6,35,36].
5. Clinical manifestations In most ways other than its extreme lethality, the 1918 influenza pandemic was clinically the same as influenza before and since [25,37]. There were, however, two clinical aspects that were widely noticed by the medical officers that have been largely restricted to the 1918 pandemic; bleeding phenomenon especially epistaxis and a very distinctive form of cyanosis [38,39]. Epistaxis or nose bleeding was noted in >10% of some military groups with influenza [38]. It was often severe requiring packing of the nose in order to stop the bright red blood coming from the nostrils. This is atypical for ordinary influenza both in frequency and type of bleeding [34,40]. Further down the respiratory tree, pulmonary hemorrhage was commonly seen on histological examination of pathology specimens but frank hemoptysis was rare [23,25,26]. The 1918 influenza virus was extra-ordinarily destructive to the respiratory epithelium throughout with cellular necrosis being commonly observed microscopically [6,23]. Although some additional bleeding phenomenon were reported such as menometrorrhagia in women, other bleeding diatheses were only rarely seen [28]. It is most likely that both the increased bacterial pneumonia rate and epistaxis are explained by the 1918 virus having an increased pathogenic effect specifically in the destruction of the respiratory epithelium [6,23]. Through cellular necrosis the normal
Figs. 1e3 Different stages of skin coloration as seen during the 1918 influenza pandemic characterized as “heliotrope” or deep blue cyanosis. Reproduced with permission from the Lancet archives.
220 ciliary movement of mucus and maintenance of blood vessel integrity were compromised leading to pneumonia and bleeding. The dark blue cyanosis seen in conscious influenza patients was so remarkably different from what had been seen before 1918 that the British Army Medical Corps brought in an artist from the Royal Academy to graphically capture the distinctive color which was described as “heliotrope cyanosis” after a deep blue flower [41] (Figs. 1e3). This was regarded as a very poor prognostic sign with 95% of soldiers showing such cyanosis going on to die usually within a single day [26,34]. The fact that these patients were conscious to nearly the point of death seemed inconsistent with the low oxygen saturation that must have existed to cause such deep cyanosis. The most likely explanation would seem to be that the entire lung was involved in a process that destroyed the epithelium and filled the alveoli with fluid [23]. Ordinary pneumonia usually only involved a few lobes of the lung allowing shunting of blood and thus some oxygenation to proceed through the unaffected parts. “Heliotrope cyanosis” was likely a marker of the extreme pathogenicity of the virus and the resulting cellular necrosis.
6. Appearance and rapid disappearance Despite many hypotheses, the origin of the 1918 influenza virus remains unknown. Genomic information generated from reconstructed nucleic acid sequences from archived pathology specimens seems to indicate that a H1N1 virus had been circulating for some time in a mammalian host prior to 1918 but this interpretation depends on the assumptions made in the models constructed from incomplete data [42,43]. In most parts of the world, an early (range March to June) 1918 pandemic wave was observed causing higher rates of illness but much lower mortality rates than what was seen in the lethal wave starting from August 1918. For example, in the French Army of approximately 4 million men 28,000 died in the late 1918 wave [44]. Some observers think that these waves were caused by two different viruses thus postulating two separate but interrelated influenza pandemics in a single year [45]. In the Australian Army, infection in the early wave made no difference in one’s illness rate in late 1918 although mortality was more than halved late in 1918 if one had a symptomatic influenza-like illness in early 1918 [8]. The most likely explanation would seem to be that at least two distinct but related H1N1 influenza viruses were circulating in 1918. The 1918 influenza virus suddenly appeared in its lethal form in late 1918 with near simultaneous peak mortality rates occurring in some cities in America, Europe, Africa and Asia [46]. Although there is good epidemiological evidence from Europe and genomic information from the USA to indicate that the lethal form of the virus was circulating months prior to its recognition in late 1918, there is no good explanation for how such a virus could suddenly and nearly simultaneously increase its lethality in multiple places across the globe [47,48]. Perhaps the “purulent bronchitis” epidemics observed in First World War soldiers from 1914 to 17 were actually the beginnings of the 1918 pandemic virus
G.D. Shanks indicating that the virus had years to spread globally through the massive movement of people associated with the war [41,49e52]. Just as it is uncertain where the 1918 influenza virus came from, its rapid disappearance is also difficult to explain. The distinctive W mortality pattern of the 1918 virus disappeared early in the 1920s although influenza viruses with less mortality continued to circulate [47]. Recent genomic analyses based on all H1N1 viruses available indicate that what became seasonal influenza in the 1920s was quite different from the pandemic virus of 1918 [43]. The pandemic virus left the human population but carried on as a previously unremarked swine infection. It changed little over time as most pigs only live long enough to experience a single influenza infection which creates little in the way of evolutionary pressure. When the 2009 pandemic arrived, part of its genetic information came from the 1918 influenza virus as maintained in swine [53]. The 2009 viral hemagglutinin is similar enough to that of 1918 to allow cross-protection in laboratory animals when immunized with the other surface protein [54]. Internal viral antigens such as the nucleoprotein also were conserved from 1918 to the 2009 pandemic virus [55]. Despite these antigenic and genomic similarities, the 1918 pandemic is the most lethal influenza virus ever recorded whereas the 2009 pandemic caused the least mortality.
7. Conclusion For several reasons, the 1918 influenza pandemic was an exception [56]. Besides its great lethality there were associated findings that were linked to increased pathogenicity such as epistaxis and deep cyanosis as well as other anomalies that have no obvious explanation such its highly variable mortality in seemingly identical groups. The 1918 enigma, however, is encapsulated in the young adult mortality peak; adequately explain why young adults preferentially died and one would be much closer to understanding its genesis and importance to future pandemics. There have been several hypothesis put forward. The most important aspect seems to be the 1918 pandemic’s relationship to the 1890 pandemic as there is no other way to explain a mortality peak at 28 y [5,9,10]. Exposure in infancy to infectious agents has different immunological implications to infections occurring later in life. The 28 y separation in time argues for long-lasting immune cells such as resident memory CD8þ lymphocytes being an important factor [57]. The inter-connections between the innate and acquired immune systems are still being defined so perhaps a more detailed mechanistic hypothesis may be possible in the future. Regardless of future hypotheses, it is clear that host factors played a large role in determining mortality rates. Persons who had few previous respiratory infections such as soldiers from rural areas died at higher rates in military recruit camps compared to their urban counter-parts [58]. Geographic isolation seemed to determine the level of mortality on Pacific Islands when the 1918 influenza virus arrived. On islands such as Guam, Saipan and Nauru, immigrants with low mortality rates lived next to local populations with high mortality rates strongly suggesting that
1918 Influenza Pandemic previous infection history was the important factor and not some unknown genetic trait. Will the 1918 influenza pandemic with its extraordinary mortality reoccur? Our inability to explain the 1918 pandemic nearly a century later should give all of us reason to be concerned about the limitations of predicting the future. Some would say that the 1918 influenza virus has already returned in the form of the 2009 pandemic. Certainly there are several antigenic and genomic similarities in these two H1N1 viruses. This still does not address the main concern, however, given the great mortality difference between the two pandemics. In spite of being unable to weave all the described attributes of the 1918 pandemic into a single mechanistic hypothesis, it is reasonable to be reassured by the historical differences. These suggest that the lethality of the 1918 influenza pandemic was specific to its timing and geography within certain populations. Nearly a century later, the world is a much different place epidemiologically especially given the increased variety and speed of pathogen circulation. Could influenza cause major new mortality concerns? Based on the very high mortality rates currently seen with H5 and H7 avian influenza, the possibility must be considered [2]. Given the few practical boundaries constraining avian influenza and its inability over the last few decades to cause sustained infection between humans, the risk appears low but the consequences of such a very rare event remain very high. Continued disease surveillance in humans and animals with an on-going annual influenza immunization program are the minimum actions required to maintain readiness against a future influenza pandemic.
Contributors GDS is responsible for the review having entirely written the manuscript.
Conflicts of interest The author claims no conflict of interest.
Funding The author did not receive any specific funding for writing this review.
Disclaimer The opinions expressed are those of the author and do not necessarily reflect those of the Australian Defence Force or the U.S Department of Defense.
Acknowledgments The author thanks the many unnamed colleagues, medical librarians, and archivists who have unselfishly provided data and ideas for this essay.
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