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Capturing a Killer Flu VirusThe deadliest flu strain in history has beenresurrected. What can the 1918 VIRUS revealabout why it killed millions and where morelike it may be lurking?By Jeffery K. Taubenberger, Ann H. Reid andThomas G. Fanning(Editor's note: This article originally appearedin the January 2005 issue of ScientificAmerican magazine. We are posting it becauseof related news regarding swine flu.)On September 7, 1918, at the height of WorldWar I, a soldier at an army training campoutside Boston came to sick call with a highfever. Doctors diagnosed him with meningitis but changed their minds the next day when adozen more soldiers were hospitalized withrespiratory symptoms. Thirty-six new cases of this unknown illness appeared on the 16th.Incredibly, by September 23rd, 12,604 caseshad been reported in the camp of 45,000soldiers. By the end of the outbreak, one thirdof the camp's population would come downwith this severe disease, and nearly 800 of them would die. The soldiers who perishedoften developed a bluish skin color andstruggled horribly before succumbing to death by suffocation. Many died less than 48 hoursafter their symptoms appeared, and at autopsytheir lungs were filled with fluid or blood.Because this unusual suite of symptoms didnot fit any known malady, a distinguished pathologist of the era, William Henry Welch,speculated that "this must be some new kindof infection or plague." Yet the disease wasneither plague nor even new. It was justinfluenza. Still, this particularly virulent andinfectious strain of the flu virus is thought tohave killed as many as 40 million peoplearound the world between 1918 and 1919.This most lethal flu outbreak in modernhistory disappeared almost as quickly as itemerged, and its cause was long believed lostto time. No one had preserved samples of the pathogen for later study because influenzawould not be identified as a virus until the1930s. But thanks to incredible foresight bythe U.S. Army Medical Museum, the persistence of a pathologist named JohanHultin, and advances in genetic analysis of oldtissue samples, we have been able to retrieve parts of the 1918 virus and study their features. Now, more than 80 years after thehorrible natural disaster of 1918–1919, tissuesrecovered from a handful of victims areanswering fundamental questions both aboutthe nature of this pandemic strain and aboutthe workings of influenza viruses in general.The effort is not motivated merely byhistorical curiosity. Because influenza virusescontinually evolve, new influenza strainscontinually threaten human populations.Pandemic human flu viruses have emergedtwice since 1918—in 1957 and 1968. And flustrains that usually infect only animals havealso periodically caused disease in humans, asseen in the recent outbreak of avian influenzain Asia. Our two principal goals aredetermining what made the 1918 influenza sovirulent, to guide development of influenzatreatments and preventive measures, andestablishing the origin of the pandemic virus,to better target possible sources of future pandemic strains.Hunting the 1918 VirusIn many respects, the 1918 influenza pandemic was similar to others before it andsince. Whenever a new flu strain emerges withfeatures that have never been encountered by

most people's immune systems, widespreadflu outbreaks are likely. But certain uniquecharacteristics of the 1918 pandemic havelong remained enigmatic.For instance, it was exceptional in both its breadth and depth. Outbreaks swept acrossEurope and North America, spreading as far asthe Alaskan wilderness and the most remoteislands of the Pacific. Ultimately, one third of the world's population may have beeninfected. The disease was also unusuallysevere, with death rates of 2.5 to 5 percent— up to 50 times the mortality seen in other influenza outbreaks.By the fall of 1918 everyone in Europe wascalling the disease the "Spanish" influenza, probably because neutral Spain did not imposethe wartime censorship of news about theoutbreak prevalent in combatant countries.The name stuck, although the first outbreaks,or spring wave, of the pandemic seeminglyarose in and around military camps in the U.S.in March 1918. The second, main wave of theglobal pandemic occurred from September to November 1918, and in many places yetanother severe wave of influenza hit in early1919.Antibiotics had yet to be discovered, and mostof the people who died during the pandemicsuccumbed to pneumonia caused byopportunistic bacteria that infected thosealready weakened by the flu. But a subset of influenza victims died just days after the onsetof their symptoms from a more severe viral pneumonia—caused by the flu itself—that lefttheir lungs either massively hemorrhaged or filled with fluid. Furthermore, most deathsoccurred among young adults between 15 and35 years old, a group that rarely dies frominfluenza. Strikingly, people younger than 65years accounted for more than 99 percent of all "excess" influenza deaths (those abovenormal annual averages) in 1918–1919.Efforts to understand the cause of the 1918 pandemic and its unusual features beganalmost as soon as it was over, but the culpritvirus itself remained hidden for nearly eightdecades. In 1951 scientists from theUniversity of Iowa, including a graduatestudent recently arrived from Sweden namedJohan Hultin, went as far as the SewardPeninsula of Alaska seeking the 1918 strain.In November 1918 flu spread through an Inuitfishing village now called Brevig Mission infive days, killing 72 people—about 85 percentof the adult population. Their bodies had since been buried in permafrost, and the 1951expedition members hoped to find the 1918virus preserved in the victims' lungs.Unfortunately, all attempts to culture liveinfluenza virus from these specimens wereunsuccessful.In 1995 our group initiated an attempt to findthe 1918 virus using a different source of tissue: archival autopsy specimens stored atthe Armed Forces Institute of Pathology(AFIP). For several years, we had beendeveloping expertise in extracting fragile viralgenetic material from damaged or decayedtissue for diagnostic purposes. In 1994, for instance, we were able to use our newtechniques to help an AFIP marine mammal pathologist investigate a mass dolphin die-off that had been blamed on red tide. Although theavailable dolphin tissue samples were badlydecayed, we extracted enough pieces of RNAfrom them to identify a new virus, similar tothe one that causes canine distemper, which proved to be the real cause of the dolphindeaths. Soon we began to wonder if there wereany older medical mysteries we might solvewith our institute's resources.

A descendant of the U.S. Army MedicalMuseum founded in 1862, the AFIP has grownalong with the medical specialty of pathologyand now has a collection of three millionspecimens. When we realized that theseincluded autopsy samples from 1918 fluvictims, we decided to go after the pandemicvirus. Our initial study examined 78 tissuesamples from victims of the deadly fall waveof 1918, focusing on those with the severelung damage characteristic of patients whodied rapidly. Because the influenza virusnormally clears the lungs just days after infection, we had the greatest chance of finding virus remnants in these victims.The standard practice of the era was to preserve autopsy specimens in formaldehydeand then embed them in paraffin, so fishingout tiny genetic fragments of the virus fromthese 80-year-old "fixed" tissues pushed thevery limits of the techniques we haddeveloped. After an agonizing year of negativeresults, we found the first influenza-positivesample in 1996, a lung specimen from asoldier who died in September 1918 at FortJackson, S.C. We were able to determine thesequence of nucleotides in small fragments of five influenza genes from this sample.But to confirm that the sequences belonged tothe lethal 1918 virus, we kept looking for more positive cases and identified another onein 1997. This soldier also died in September 1918, at Camp Upton, N.Y. Having a secondsample allowed us to confirm the genesequences we had, but the tiny quantity of tissue remaining from these autopsies made usworry that we would never be able to generatea complete virus sequence.A solution to our problem came from anunexpected source in 1997: Johan Hultin, bythen a 73-year-old retired pathologist, hadread about our initial results. He offered toreturn to Brevig Mission to try another exhumation of 1918 flu victims interred in permafrost. Forty- six years after his firstattempt, with permission from the BrevigMission Council, he obtained frozen lung biopsies of four flu victims. In one of thesesamples, from a woman of unknown age, wefound influenza RNA that provided the key tosequencing the entire genome of the 1918virus.More recently, our group, in collaborationwith British colleagues, has also beensurveying autopsy tissue samples from 1918influenza victims from the Royal LondonHospital. We have been able to analyze fluvirus genes from two of these cases and havefound that they were nearly identical to the North American samples, confirming the rapidworldwide spread of a uniform virus. Butwhat can the sequences tell us about thevirulence and origin of the 1918 strain?Answering those questions requires a bit of background about how influenza virusesfunction and cause disease in different hosts.Flu's Changing FaceEach of the three novel influenza strains thatcaused pandemics in the past 100 years belonged to the type A group of flu viruses.Flu comes in three main forms, designated A,B and C. The latter two infect only humansand have never caused pandemics. Type Ainfluenza viruses, on the other hand, have been found to infect a wide variety of animals,including poultry, swine, horses, humans andother mammals. Aquatic birds, such as ducks,serve as the natural "reservoir" for all theknown subtypes of influenza A, meaning thatthe virus infects the bird's gut without causingsymptoms. But these wild avian strains canmutate over time or exchange genetic material