Raising the ghost of 1918: Could flu be the ultimate bioweapon?

Skeptics doubt terror factor, but pandemic planning praised

In an age of exploding genetic engineering, could the Spanish influenza strain of 1918 — the unholy grail of infectious diseases — be resurrected as the ultimate bioweapon?

"It would not be easy; but with advances in this technology, it gets easier every day," warns Mohammed Madjid, MD, lead author of a provocative new paper about the possibilities of using the flu virus as a weapon of bioterrorism.

To be certain, flu is not at the top of anyone’s list of bioterrorism concerns. It is a seasonal killer that we face annually with a striking complacency, given its death toll. On the contrary, for a while, the anthrax attacks of 2001 seemed to imbue every white powder with a deadly resonance. A total of five people died in the anthrax attacks. The Spanish flu epidemic in 1918 killed somewhere between 20 million and 40 million people globally.

"Our society is so fearful of anthrax right now," says Madjid, a cardiologist at the University of Texas (UT)-Houston Health Center. "Imagine influenza. The virulent strain of Spanish flu had a fatality rate of 25% to 50%. That is almost 10 times that of SARS."

Unfortunately, this is not an episode of The Outer Limits. Madjid and co-authors — including Scott Lillibridge, MD, national bioterrorism expert and director of the Center for Biosecurity and Public Health Preparedness at the UT School of Public Health in Houston — ask us to consider the possibility of malicious genetic engineering to restore the 1918 strain. "Sequencing of the genome of the 1918 Spanish influenza virus is nearly complete; once it is published, unscrupulous scientists could presumably utilize candidate virulence sequences," they warn.1

Genetic sequencing work has, indeed, been undertaken in part to try to understand the extraordinary virulence of the 1918 flu strain.2 RNA from the 1918 pandemic virus was isolated from a preserved lung tissue sample. Nine fragments of viral RNA were sequenced from the coding regions of the virus. The sequences are consistent with a novel H1N1 influenza A virus that belongs to the subgroup of strains that infects humans and swine. Another team of virologists determined that the 1918 strain was formed by a "recombination" of human and swine viruses that likely "changed the virulence of the virus."3

Healthy people felled by strain

The virulence of the 1918 flu borders on legend, but even the Centers for Disease Control and Prevention (CDC) soberly recalls: "Some people who felt well in the morning became sick by noon, and were dead by nightfall. . . . With the Spanish flu, mortality rates were high among healthy adults as well as the usual high-risk groups. The attack rate and mortality was highest among adults 20 to 50 years old. The severity of that virus has not been seen again."4

All well and good around the campfire — but could the fabled strain be raised, so to speak, from the dead? In that regard, Madjid cites another disturbing, recent study: the successful creation of a poliovirus in vitro solely by following instructions from a written genetic sequence.5 In other words, all the future bioterrorist may need is something akin to a genome cookbook.

"The message is to be prepared, not panicked," Madjid says. "It would not be very wise if we didn’t say anything about this and waited until something came up."

Still, recreating a strain of the 1918 flu, if it is ever possible, would certainly take a sophisticated laboratory and sustained effort, says William Bicknell, MD, PhD, professor of international health at Boston University. "It would absolutely have to be state sponsored. You can’t say it won’t happen, but I think it is unlikely. There are plenty of things out there good enough as they are as terror weapons."

Indeed, manipulating pathogens in the lab raises the possibility that you actually will create weaker strains or — having succeeded with a deadly version — infect yourself, he adds.

Flu could prove a potent killer even if the legendary 1918 strain remains in its grave. Madjid — a heart specialist by training — became interested in the bioterrorism issue after uncovering a surprising finding in a prior study: Influenza immunization reduces the risk of recurrent myocardial infarction by 66%.6 The findings were underscored by other research indicating that influenza immunization could half the rate of heart attack and stroke and cardiovascular death.7-9

The other side of the coin is that flu may be causing many more deaths then traditionally estimated or annually recorded. There are some data that suggest the 1918 influenza pandemic contributed to the epidemic of coronary heart disease mortality in the 20th century.10

Given the emerging link between flu, heart attack, stroke, and cardiac-related mortality, Madjid and colleagues hypothesize that many more people die of influenza-related illness than traditionally estimated. The typical projection of 20,000 deaths in the United States, for example, probably is closer to 90,000, they project.

Given such death tolls, virtually any nasty strain of influenza — particularly if engineered to evade the current vaccine — could be a dangerous bioweapon. More specifically, terrorists could take a particularly threatening strain — such as the H5N1 avian flu that briefly emerged from Hong Kong in the late 1990s — and perfect its pandemic possibilities.

"Very virulent strains appear from time to time," Madjid says. "Somebody could culture it in tissue again and again until a strain comes up that could be transmitted to a person. So there are two ways to access [flu], from nature and by manipulating it in the lab."

Several factors favor influenza as an effective weapon of bioterrorism, he notes. The virus is usually transmitted by direct contact, but also can be transmitted by aerosol (e.g., on a passenger plane). Aerosolizing flu also lessens the viral load necessary to induce infection. "Taken together with the fact that influenza virus is readily accessible and may be causing more deaths than previously suspected, the possibility for genetic engineering and aerosol transmission suggests an enormous potential for bioterrorism," the authors conclude.

Influenza occurs naturally, so initial clusters of intentional infections would raise little alarm. With a relatively short incubation period (one to four days), vaccine may not be an effective response following delayed recognition of a widespread flu release. "Immunization after exposure to influenza is, therefore, not protective, and even the neuraminidase inhibitors such as oseltamivir must be administered before symptoms develop or within the first 48 hours after their appearance," Madjid and colleagues argue, adding the interesting twist that influenza poses a threat to world leaders because most are elderly.

An intentional release of a virulent flu strain essentially could result in a pandemic, which public health officials expect to occur naturally again at some point because of flu’s constant mutation. A pandemic typically occurs when the viruses’ annual antigenic drift becomes a sharp antigenic shift that circumvents population immunity.

The CDC estimates that the next global influenza pandemic will take a stunning toll in lives and dollars while virtually overwhelming the health care system. CDC researchers estimate that a pandemic flu strain in the United States would cause 89,000 to 207,000 deaths; 314,000 to 734,000 hospitalizations; 18-42 million outpatient visits; and 20 million to 47 million additional illnesses.11 Patients at high risk (15% of the population) would account for approximately 84% of all deaths. Add an aspect of intentionality to those figures, and you begin to transform accepted disease into a weapon of terror. But regardless of whether it was natural or intentional, a pandemic would create considerable problems for hospitals, including nosocomial transmission to susceptible patients and staff.

According to infection control recommendations in CDC pandemic plans, incoming flu patients ideally would be treated under droplet isolation precautions with workers wearing masks within 3 feet of patients. However, the CDC concedes that this may not be practical during a pandemic. Use of masks to prevent transmission of influenza in the community — as was seen in 1918 and more recently with SARS — also is not likely to be effective in containing flu, the CDC warns.

Unlike the typical focal disaster, an influenza pandemic will be widespread, requiring preparedness in every community. Moreover, unlike natural disasters, demands on medical care in each community will last six to eight weeks until the first wave of infection is complete. If influenza-associated illness was as severe as in 1918, local health services easily could become overwhelmed very quickly, the CDC warns. Potential shortages are projected for intensive care unit beds, ventilators, antiviral agents, and antibiotics for treatment of secondary pneumonia. There may be a "high demand for mortuary/funeral services" the agency dutifully notes.12

Flu wanting in the terror factor?

Still — even granting the considerable aura surrounding the 1918 strain — there are psychological questions about a bioweapon that is as familiar as the common cold. The principal question is whether flu strikes sufficient fear to invoke terror.

"We are, unfortunately, inured to the flu cycle," says William Schaffner, MD, chairman of the department of preventive medicine at Vanderbilt University in Nashville. "It would not cause terror. That’s why it is not on the A’ list of bioterrorism agents. But if our colleagues’ attention to this heightens preparedness for pandemic flu, they will have done a good service and I congratulate them."

Bicknell concurs, arguing that the terrorist just doesn’t get the bang for his buck with influenza. "A terrorist wants to terrorize," he says. "A cloud of anthrax, smallpox, random bombings will terrorize. But with flu, lots of people will get it and not be very sick, some will be very sick, and some will die. If I were choosing weapons, I wouldn’t go for it. I would go for something more horrible. If we had Ebola in St. Louis, that would be scary."

Moreover, releasing flu is problematic in that the course of infection would be completely unpredictable. There would be the very real possibility of catastrophic "blow back" to untargeted allies of the terrorists, Schaffner adds. Who could have predicted, for example, that severe acute respiratory syndrome would arise in China and wreak havoc on Toronto?

"Why not Germany instead of Canada? These are mysteries," Schaffner says. "Unless a terrorist was concerned only with creating anarchy, flu would not be a very good weapon."

Add that treatments for flu are available and medicine has a long history of vaccine development, and the scales begin to tilt against flu as a bioweapon.

"Influenza will recur," Bicknell says. "It modifies itself, and we may have another flu pandemic. How many of the [1918] deaths from flu were because we didn’t know about managing respiratory infection; we didn’t have antibiotics for bacterial superinfection? We don’t really know whether it would be like the flu pandemic of 1918. Far more important then worrying about the individual agent is our capacity to respond to an incident when it occurs."

Indeed, Madjid emphasizes that viewing flu as a potential bioweapon only readies preparedness if another pandemic naturally occurs.

"Whatever thought we put into bioterrorism preparedness will be very useful for facing either a natural or man-made pandemic," he says. "I hope there will never be such a disaster. But since we know that natural pandemics are coming, it is a very timely and useful thing to do."

References

1. Madjid M, Lillibridge S, Mirhaji P, et al. Influenza as a bioweapon. J R Soc Med 2003; 96:345-346

2. Taubenberger JK, Reid AH, Kraft AE, et al. Initial genetic characterization of the 1918 Spanish’ influenza virus. Science 1997; 275:1,793-1,796.

3. Gibbs MJ, Armstrong JS, Gibbs AJ. Recombination in the hemagglutinin gene of the 1918 Spanish flu.’ Science 2001; 293:1,842-1,845.

4. Centers for Disease control and Prevention. Pandemic Influenza at: http://www.cdc.gov/od/nvpo/pandemics/.

5. Cello J, Paul A, Wimmer E. Chemical synthesis of poliovirus cDNA: Generation of infectious virus in the absence of natural template. Science 2002; 297:1,016-1,018.

6. Naghavi M, Barlas Z, Siadaty S, et al. Association of influenza vaccination and reduced risk of recurrent myocardial infarction. Circulation 2000; 102:3,039-3,045.

7. Siscovick DS, Raghunathan TE, Lin D, et al. Influenza vaccination and the risk of primary cardiac arrest. Am J Epidemiol 2000; 152:674-677.

8. Lavallee P, Perchaud V, Gautier-Bertrand M, et al. Association between influenza vaccination and reduced risk of brain infarction. Stroke 2002; 33:513-518.

9. Gurfinkel EP, de la Fuente RL, Mendiz O, et al. Influenza vaccine pilot study in acute coronary syndromes and planned percutaneous coronary interventions: The FLU Vaccination Acute Coronary Syndrome (FLUVACS) Study. Circulation 2002; 105:2,143-2,147.

10. Azambuja MI, Duncan BB. Similarities in mortality patterns from influenza in the first half of the 20th century and the rise and fall of ischemic heart disease in the United States: A new hypothesis concerning the coronary heart disease epidemic. Cad Saude Publica 2002; 18:557-577.

11. Meltzer MI, Cox NJ, Fukuda K. The economic impact of pandemic influenza in the United States: Priorities for intervention. Emerg Infect Dis 1999; 5:659-671.

12. Centers for Disease Control and Prevention. Pandemic Influenza: A Planning Guide for State and Local Officials (Draft 2.1) at: http://www.cdc.gov/od/nvpo/pandemicflu.htm.