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I. Literature sources
Taubenberger J K, Morens D M. 1918 influenza: the mother of all pandemics[J]. Emerging infectious diseases, 2006, 12(1):15-22.
The literature was published in the American CDC academic journal Emerging Infectious Diseases, January 2006, Volume 12, No.1, with the title "1918 Influenza: Mother of All Pandemic Diseases". （ www.cdc.gov/eid）
II. Introduction to the author
Dr. Taubenberger: Director of Molecular Pathology, United States Army Pathology Institute, Rockville, Maryland. The research direction is the molecular pathophysiology and evolution of influenza virus.
Dr Morens: epidemiologist, working for the American institute of allergy and infectious diseases. His research interests are emerging infectious diseases, virology, tropical medicine and medical history.
foreword
From 1918 to 1919, Spanish influenza caused about 50 million deaths in the world, and it is still an ominous haze of public health. There are still many unanswered questions about the origin, such as unusual epidemiological characteristics and main pathogenic factors. Although we are now trying to overcome the spread of pandemics such as H5N1 or other viruses, the impact of the 1918 influenza on public health is still uncertain. The information of the 1918 influenza is still being updated, such as sequencing the whole genome from the autopsy in the archives, but the virus genome alone cannot answer the key questions. To understand the 1918 flu and its impact on the future, we need detailed experiments and in-depth historical analysis. Tip: The number of words in the full text is 7279, and it takes an average of 15 minutes to finish reading.
background
During the 1918-1919 flu, about one third of the world’s population (about 500 million people) was infected and developed clinical symptoms. The pandemic is more serious than expected. Compared with the mortality rate of other pandemics (< 0.1%), the mortality rate of influenza in 1918 was > 2.5%. It is estimated that the total death toll is about 50 million, and the pessimistic view is as high as 100 million.
The influence of 1918 influenza was not limited to 1918-1919. Since then, almost all influenza A (except avian influenza virus, such as H5N1 and H7N7) in the world are descendants of 1918 influenza virus, including drifting H1N1, recombinant H2N2 and H3N2. The latter is the integration of the key genes of the 1918 influenza by the later avian influenza, thus expressing new proteins. It can be said that the 1918 flu is the mother of all pandemics.In 1918, it was unclear how human influenza was related to avian influenza and swine flu. Although the clinical and epidemiological characteristics are similar to those of influenza pandemics in 1889, 1847 or even earlier, the high mortality rate makes many people wonder whether it should be called influenza. This problem was not solved until 1930, when the influenza virus (now called H1N1) was isolated from pigs, and later it was also isolated from humans. Seroepidemiological studies soon linked the virus with the 1918 flu. Subsequent research shows that the offspring of 1918 virus has always existed in pigs, and may still appear in humans continuously, experiencing the continuous iteration of antigenic drift, and leading to an annual epidemic outbreak until the 1950s. In 1957, a new H _ H2N2 epidemic (namely "Asian influenza") began to appear, and the H1N1 virus, the offspring of the 1918 virus, completely disappeared from the human circulation, although the related pedigree was still attached to pigs. But in 1977, it suddenly "reappeared" from the laboratory freezer and began to be popular among humans.
In 2006, two natural lineages and two recombinant lineages of the offspring of 1918 virus became popular: human H1N1, swine H1N1 (swine flu), recombinant human H3N2 and recombinant swine H3N2, but none of the offspring was close to the pathogenicity of 1918 virus. Swine strains H1N1 and H3N2 rarely infect humans, while the morbidity/mortality of human strains H1N1 and H3N2 are lower than that of 1918 virus.In fact, the fatality rate of natural H1N1 is even lower than that of H3N2 (prevalent since 1968). The H1N1 and H3N2 viruses originated from the 1918 influenza have been prevalent all over the world for 29 years, and there are almost no signs of extinction.
First, try to understand what happened?
By the early 1990s, 75 years of research had failed to answer the most basic question of the 1918 flu: Why was it so deadly? People didn’t isolate any virus from the 1918 influenza epidemic, but their descendants continued to invade humans slightly. A follow-up survey of influenza epidemic in the 1920s showed that in the years after 1918, influenza epidemic became an annual epidemic with low mortality due to gene drift. Did one genetic event greatly reduce the pathogenicity of the 1918 virus, and then another genetic event turned the 1918 virus into a weaker H1N1 virus?
In 1995, a scientific team determined the autopsy materials of influenza in the autumn of 1918 from the archives, and began a long sequencing experiment on small RNA virus fragments, so as to deduce the whole genome of the 1918 virus. At present, the whole genome of one virus and partial gene sequences of four other viruses have been determined. The above experiments and a series of other articles related to 1918 virus have confirmed that 1918 virus is most likely the ancestor of human/pig H1N1, H3N2 and extinct H2N2. No mutation related to the genome of 1918 virus has been found in other highly pathogenic influenza viruses of human or animals, but the continuous study on virulence factors has produced some interesting results. Nevertheless, the 1918 gene sequence data can not answer the origin and epidemiological characteristics of the virus.
Second,When and where did the 1918 flu begin to spread?
Before and after 1918, most influenza pandemics originated in Asia and spread all over the world.During the 12-month period from 1918 to 1919, the 1918 flu spread more or less simultaneously from three regions: Europe, Asia and North America (the first wave is thought to have started in the United States in March 1918). Historical and epidemiological data are not enough to identify the geographical origin of the virus, and the recent 1918 gene system research can not analyze the geographical origin.
Although there was no national influenza disease reporting system in 1918, and the diagnostic criteria for influenza and pneumonia were not clear, since December 1915, there was an epidemic of respiratory diseases in the United States, and the mortality rate of influenza and pneumonia rose sharply in 1915 and 1916, and then decreased slightly in 1917. The first wave of influenza pandemic appeared in the spring of 1918, and the second wave and the third wave of influenza pandemic with higher mortality rate appeared in the autumn of 1918 and the winter of 1919 respectively, as shown in Figure 1.
Is it possible that the weak-adaptability H1N1 virus had spread in 1915, and although there were some serious diseases, it had not caused a pandemic?At that time, data consistent with this was also reported from European military camps, but the opposite conclusion was given: if the virus strain with new hemagglutinin (HA) affected the mortality rate of influenza and pneumonia in the United States, it should have caused a pandemic long ago, and someone should be immunized or at least partially immunized by 1918. It is difficult to determine that the "pioneer" events of the 1918 flu came from 1915, 1916 or even early 1918.
Figure 1 Three waves of epidemics: the weekly mortality rate of influenza and pneumonia in Britain from 1918 to 1919.
Another unique feature of the 1918 influenza pandemic was that people and pigs were infected almost at the same time.The 1918 virus probably expressed a new subtype of antigenicity, which led to the low immunity of most people and pigs. Recently published genetic studies show that hemagglutinin (HA) and neuraminic acid (NA) expressed by the 1918 virus gene were probably derived from the avian influenza virus shortly before the start of the pandemic, and the precursor virus failed to spread widely in humans or pigs for decades. More recent reports of the virus gene sequence and phylogenetic analysis of the virus also support this conclusion. Regression analysis of human/swine flu sequences from 1930 to the present shows that the precursor of 1918 virus first spread in humans from 1915 to 1918. Therefore, the precursor of the 1918 virus may have spread widely among humans before 1918, and so far no research has directly indicated the transition from any bird. In a word, its origin is still confusing.
Are the three waves of epidemics from the same virus?
Historical records since the 16th century show that a new influenza pandemic may occur at any time of the year, which is not necessarily the regular pattern in winter every year, because the behavior pattern most likely from the new influenza has been found among infected people. After that, these pandemic viruses began to drift in the face of the selective pressure of population immunity, and eventually the pattern of annual epidemic recurrence was triggered by drifting virus mutants.
During the 1918-1919 pandemic, the first spring tide began in March 1918 and spread to the United States, Europe and even Asia in different degrees in the next six months. The prevalence rate was very high, but the mortality rate in most areas was not significantly higher than the normal value. The second wave of autumn tide began in September-November, 1918, and it spread rapidly around the world and was fatal. The third wave of epidemic began in early 1919. According to the clinical similarity, some contemporary observers have come to the conclusion at the beginning that the three epidemics should be caused by the same disease: the mild symptoms in the three epidemics are the same, and they have the typical flu characteristics of the 1889 pandemic and earlier pandemics. However, in retrospect, there are few cases in which the first wave of spring tide developed rapidly from simple influenza to fatal pneumonia, and fatal pneumonia is the symbol of the last two waves of epidemic tide; Comparatively speaking, the frequency of complex, serious and fatal cases in the last two waves will be higher.
It is unprecedented for three large-scale epidemics to occur in a year. To some extent, the antigenic drift of the virus is the reason why it keeps recurring every year, and an antigenic virus variant appears about every 2 ~ 3 years. If there is no drift characteristic, once the immunity of human/livestock reaches the critical threshold, the influenza virus may disappear, and under this critical threshold, the further spread of the virus is limited. For decades, people have been speculating about the time and space between influenza pandemics. In addition to human/livestock immune restrictions, the factors of virus transmission include low ambient temperature, nasal cavity temperature (which is beneficial to heat-labile viruses, such as influenza), suitable humidity, indoor congestion and poor ventilation.
However, none of the above factors can explain the three waves of epidemic in 1918-1919, which occurred in spring and summer, summer and autumn and winter respectively. The first two waves occur at the time of unfavorable influenza transmission every year; The second wave broke out in the northern hemisphere/southern hemisphere from September to November; In addition, the period between epidemic tides is so short that it is almost impossible to detect in some areas. It is difficult for epidemiology to explain the sharp decline of cases between the first wave and the second wave, and the sharp rise of cases between the second wave and the third wave. Even assuming that the acquired immunity after infection is short-lived, there are too few susceptible people to maintain the spread at one point. How can a new explosive pandemic be triggered in a few weeks? Will the virus mutate completely at the same time in almost a short time around the world?
However, according to scientific experience, it takes several years for influenza virus to spread globally, not just a few weeks. Moreover, even the mutant that has drifted will take several months to spread around the world. Other influenza pandemics have not been reported continuously within one year. For example, the 1889 flu began in the late spring of 1889, and it took several months to spread around the world, reaching its peak in northern Europe and the United States in late 1889 or early 1890; The second recurrence occurred in late spring of 1891 (one year late) and the third in early 1892. Like the 1918 flu, more people died when the second epidemic wave recurred, but the spread time of the three epidemics in 1889-1892 was more than three years, while the spread time of the successive epidemics in 1918-1919 was compressed to August-September.The ability of the 1918 influenza to rapidly develop a continuous pandemic is still unknown. Because the autopsy materials we identified only came from the second wave of 1918 influenza, it is inconclusive whether the first wave or the third wave also came from the same virus or mutant. The experimental data show that the second wave of infected people may have obtained immune protection during the third wave of epidemic, but the data is not enough to support whether the second/third wave of infected people obtained immune protection from the first wave of epidemic, nor can they answer the question whether the three waves of epidemic came from the same virus or mutant. Only by getting the RNA positive samples of infected people before 1918 and the three waves of epidemic in 1918 can we answer this question.
4. Did the 1918 virus host come from animals?
The data of 1918 virus gene sequence shows that the whole genome may be new to human beings in 1918 or not long ago. It was not produced by recombining one or more new genes from previous viruses (unlike the 1957 or 1968 epidemic). On the contrary, the 1918 virus seems to be derived from an unknown source of avian influenza virus (eight gene fragments are different from the current avian influenza genes). The gene sequence of influenza virus collected from wild bird specimens around 1918 is not much different from that of today’s avian influenza virus, which indicates that even for a long time, the antigenic changes of avian influenza virus may hardly occur in natural reservoir.
For example, the sequence of 1918 nucleoprotein (NP) gene is similar to the virus in wild birds in amino acid level, but it is very different in nucleotide level, which indicates that the source of 1918 nucleoprotein is far from the virus nucleoprotein in wild birds at present. One way to check the evolutionary distance of genes is to compare the ratio of synonymous nucleotides to non-synonymous nucleotides. Synonymous substitution means that the nucleotide change in the sequence will not lead to amino acid substitution; Non-synonymous substitution means that nucleotide changes will lead to amino acid substitution. Generally speaking, viruses under immune drift pressure or adapting to new hosts show a larger proportion of non-synonymous mutations, while viruses under minimal pressure mainly accumulate synonymous substitutions, which are considered to reflect the evolutionary distance.
Because the 1918 influenza virus gene fragments known from wild birds have more synonymous substitutions than expected, they are unlikely to come directly from viruses similar to avian influenza virus. One of them is particularly obvious. When people check the 4-fold degenerate codons (a subset of synonymous substitutions), they find that the third codon can replace any of the 4 nucleotides without changing the amino acids. At the same time, although the 1918 virus has been adapted to the intermediate host of human/pig for many years, the amino acid level of its sequence is still very small compared with that of wild birds. One possible explanation is that these abnormal gene fragments were obtained from an unidentified influenza virus database.All these findings lead to a question: Where did the 1918 virus come from?
Contrary to the 1918 virus, the gene fragments of the recombinant viruses of 1957 and 1968 influenza were from Eurasian avian influenza virus. Both human viruses are produced by the same mechanism: it is the recombination of Eurasian avian influenza virus and the previously popular human H1N1 virus. To prove the origin of the 1918 virus, samples more similar to the 1918 virus sequence are needed: samples before the 1918 virus epidemic and wild epidemic samples.
5. What is the biological basis of the pathogenicity of the 1918 virus?
Single gene sequence analysis can not provide the cause of pathogenicity of 1918 virus. Through a series of in vitro/animal model experiments, the researchers tried to model the virulence of the virus constructed by reverse gene.
Influenza virus infection requires HA protein to bind to sialic acid receptors on the surface of host cells.However, the configuration of HA receptor binding site of influenza virus suitable for avian infection is different from that of influenza virus suitable for human infection. Avian influenza virus preferentially binds sialic acid receptor with α(2-3) linked sugar; Human influenza virus is considered to preferentially use α(2-6) linked sugar. This avian receptor configuration can be transformed into infection only by changing one amino acid, while the HA protein of five sequenced 1918 viruses has this change, which is probably a key step to adapt to human hosts. There is also a second possibility that three of the five sequenced 1918 viruses have another change in their HA sequence that enhances the binding of human receptors.
This means that at least two H1N1 receptor-binding mutants spread in 1918: one shows high affinity with human receptor and the other shows mixed high affinity with avian/human receptor. But there is no geographical or chronological indication that one of the variants is the precursor of the other.Did these viruses have the same transmission ability in 1918, did they have the same replication pattern in the respiratory tree, and did they spread the same virus in the first and third epidemics? Are unknown.
In a series of in vivo experiments, recombinant genes containing gene fragments 1 and 5 of 1918 virus have been produced. These recombinants with 1918 HA/NA showed high pathogenicity in mice. In addition, the microarray analysis of gene expression in lung tissue of these mice showed that cell apoptosis, tissue damage and oxidation were all related to the expression of such genes. These findings are unexpected, because the virus with 1918 gene has not adapted to mice; The control group (mice infected with other modern human viruses) showed little pathogenicity and virus replication. Mice infected with 1918 HA/NA recombinant showed necrosis of bronchial and alveolar epithelium and obvious inflammatory infiltration in their lungs, which indicated that 1918 HA (and possibly NA) contained pathogenic factors for mice. It is not clear whether the pathogenicity of mice can effectively simulate the pathogenicity of humans, and the potential role of other 1918 single or combined proteins is not clear. The researchers plan to further draw the genetic basis of the toxicity of the 1918 virus on other animal models. These experiments may help to determine the pathogenic components of the 1918 virus, but it is impossible to determine whether it is the main factor in the death pattern of the 1918 influenza.
Why did the 1918 virus kill so many healthy young people?
From the historical experience, the flu death curve by age has been U-shaped for at least 150 years (Figure 2), which shows the peak of death in childhood and old age, and the death rate in the middle age group is lower. On the contrary, the 1918 flu showed a unique pattern, a "W-shaped" curve that had never been recorded, and there was another death peak among people aged about 20-40.During 1918-1919, the mortality rate of people aged 15-34 suffering from influenza and pneumonia was more than 20 times higher than in previous years. Nearly half of the 1918 flu deaths came from people aged 20-40, which was unique to the 1918 flu.
Another unique point is that the mortality rate of people under 65 years old is much higher than that of people over 65 years old, and it accounts for 99% of the flu deaths in 1918. In comparison, the mortality rate of people under 65 years old accounted for 36% of the 1957 H2N2 influenza and 48% of the 1968 H3N2 influenza.
Figure 2 Mortality rate of influenza and pneumonia per 100,000 population of all ages in the United States from 1911 to 1918.
Further dividing the influenza mortality curve by age, we can clearly see that the prevalence rate of people under 35 years old is very high (Figure 3-a), but there is still a W-shaped death peak among young people, which is obviously different from the U-shaped curve of influenza in 1928-1929 (Figure 3-c). The same 1918 flu, the prevalence rate of 5 ~ 14 years old is also high, but the mortality rate is much lower (Figure 3-a/b). In order to explain this model, we must jump out of the host and environmental factors and look further, which may include immunopathological factors (such as increased antibody-dependent infection associated with virus exposure) and other risk factors (such as concurrent infection, drugs used and environmental factors). See figure 3.
Fig. 3 Community survey results of American public health institutions in 8 states in 1918.
Note: Figures A, B and C show the prevalence rate, mortality rate and mortality rate of influenza and pneumonia in different age groups respectively.
There is a theory that can partially explain these findings. The 1918 virus is highly toxic, but for patients born before 1889, that is, people who are over 35 years old and have been exposed to the virus at that time, they have obtained partial immune protection against the 1918 virus. But there is a paradox in this theory: this nameless virus precursor must have appeared before 1889, and then reappeared 30 years later, but no trace has been found today.
Epidemiological data collected from 1900 to 1918 provided good evidence for the emergence of a new antigenic virus in 1918. It shows that from 1900 to 1917, the age group of 5 to 15 years old accounted for 11% of the total number of influenza cases, while the age group over 65 years old accounted for 6% of the total number of influenza cases. However, in 1918, the age group of 5-15 years jumped to 25% of the total number of influenza cases, while the age group over 65 years accounted for only 0.6% of the total number of influenza cases. This is consistent with the results of protective immunity obtained by previous exposure to the same or related viruses, and the mortality data is also consistent. In 1918, the number of deaths from influenza and pneumonia in the age group over 75 was less than that in 1911-1917 before the pandemic. At the other end of the age group (Figure 2), the infant mortality rate in 1918 was similar to other pandemic patterns.
Will the 1918 flu reappear? If so, what should I do?
As far as the course of disease and pathology are concerned, the 1918 influenza pandemic is different from the historical pandemic only in degree, not in species.Despite the large number of deaths worldwide, most infected people (> 95% from industrialized countries) are mild, which is not much different from today’s influenza. In addition, the experimental results of recombinant influenza virus containing 1918 virus gene show that 1918 virus and 1918-like virus are as sensitive to the anti-influenza drugs rimantadine and oseltamivir (approved by FDA) as other typical influenza viruses.
However, the 1918 flu has some characteristics of its own: in particular, the mortality rate is 5 ~ 20 times higher than expected. From the clinical and pathological point of view, these high mortality rates seem to be caused by many factors, including a higher proportion of severe respiratory infections (organ failure not caused by influenza); In addition, death cases are concentrated in an unusually young age group; Finally, in 1918, three influenza epidemics appeared one after another at an unusually rapid speed. Each feature may reflect the genetic characteristics of the 1918 virus, but to understand them, it is necessary to check the host and environment.
Until we can’t determine which factors lead to the influenza pandemic and high mortality rate, these can only be guesses. We can only come to the conclusion that since it has happened before, similar conditions may lead to the same serious pandemic.
Like the virus in 1918, H5N1 is an avian virus, although it is a distant relative. The reasons for the evolutionary path of the 1918 pandemic are completely unknown, but it seems to be different from the current H5N1 situation in many aspects. No matter the 1918 pandemic or any other infectious disease pandemic, there is no historical data showing the existence of a pandemic "precursor virus", which led to the outbreak of highly pathogenic infection in poultry; There is no historical data to prove that highly pathogenic avian influenza (HPAI) virus, including other virus subtypes such as H5N1, can cause human epidemics, let alone pandemics.
Effective human-to-human transmission is the main prerequisite for the emergence of pandemic.Although the adaptation of influenza viruses to human cells (such as receptor binding) has begun to be understood at the molecular level, how various influenza viruses adapt to humans is not completely clear at present. In 1918, the virus acquired the characteristics of adapting to human beings, but at present, we have no way to know whether the H5N1 virus will acquire the ability of human-to-human transmission in a parallel process. Although the data about the 1918 virus has increased geometrically in the past ten years, we don’t know much more about the 2006 influenza pandemic than about the risk of the 1976 H1N1 "swine flu" epidemic.
Even with modern antiviral drugs, vaccines, and knowledge of infectious disease prevention, if there is another virus like 1918, it may still kill more than 100 million people all over the world. An outbreak of a pandemic virus with high pathogenicity potential, such as the recent H5N1 virus, may cause more deaths.
No matter the virus, host or environmental factors, the virus of the first wave in 1918 had nothing to do with the abnormal pathogenicity of the second and third waves. And more, identify the virulence models of the first wave of influenza RNA positive cases from different gene sequences; Identification of human influenza RNA samples before 1918 is helpful to understand the time when the 1918 virus appeared; The observation and sequencing of a large number of animal influenza viruses will help us to understand the genetic basis of adapting to the host and the natural reservoir range of influenza. Generally speaking, it is necessary to have a comprehensive understanding of the 1918 influenza from the aspects of history, epidemiology and biology in order to answer many unsolved mysteries.
Acknowledgement:This article was reviewed by Dr. Zhu Xun, a famous immunologist and an expert of the former National New Drug Advisory Committee. I sincerely thank Mr. Zhu for his careful guidance!
Translation: Shi Junxin
Editor: Ginger
