Medical Readiness:
Facing the Threat of Pandemic Influenza

Dr. James Campbell’s office overlooks Old St. Paul’s Cemetery, a walled, peaceful area of land about the size of a square city block. Dating to 1800, the cemetery holds the remains of more than a thousand early Baltimoreans, including Lt. Col. George Armistead, who commanded Ft. McHenry during the Battle of Baltimore, and John Eager Howard, a Maryland governor and U.S. Senator who sold our medical school founders the land on which to build Davidge Hall.

Weathered headstones and settled crypts offer the assistant professor of pediatrics a sobering view for sobering work. As principal investigator for one of the National Institute of Health’s ongoing avian flu vaccine trials, Campbell oversees research that the world is counting on.

Daily news updates on the spread of avian influenza A virus H5N1 have tracked the disease from its 1996 discovery in Guangdong Province, China, through east Asia, the Middle East, Africa, and western Europe. As of this writing, the World Health Organization (WHO) is reporting 173 laboratory-confirmed cases worldwide of human infection with avian influenza A/H5N1. Of these, 93 have died. Should this virus mutate into a pandemic strain, transmissible from human to human, the consequences would be devastating. Worst-case estimates have ranged as high as 142 million people dead, with worldwide economic losses of $4.4 trillion. More conservative estimates still predict over a million fatalities. The difference lies in the imagined virulence of the hypothetical mutant virus.

To date, victims of H5N1 have had close contact with infected birds. In response, more than 180 million chickens and ducks have been slaughtered worldwide. Meanwhile zoos are seeking means to isolate—rather than exterminate—their rare or endangered birds. Locfsal seminars are educating poultry farmers about how to safely compost chicken carcasses on a mass scale, should the need arise.

Health officials and policymakers in Maryland are thinking far beyond the birds, however. They are planning for a pandemic the likes of which have not been seen since 1918, when the Spanish flu killed more than twenty million people worldwide, with up to 700,000 deaths in the United States.

Michael Greenberger, Maryland law school professor and host of its center for health and homeland security

On January 13th, the University of Maryland School of Law hosted a full day symposium titled “Avian Flu: What Can We Do?” which brought together academics, policy-makers, hospital officials, lawyers, health care providers, public health officials, and pharmaceutical manufacturers to educate one another and to begin coordinating a master emergency plan. More than 300 attendees overflowed the auditorium to hear 23 speakers address the complexity of pandemic preparedness.

Michael Greenberger, Maryland law school professor and director of the center for health and homeland security, opened the program bluntly: “Quite frankly, I don’t think anybody feels there are effective plans in place. We have to start somewhere.”

And everywhere. In something of a marathon, seven consecutive panels tackled the underlying science of avian influenza; vaccine development; quarantine and isolation; antiviral drugs; and the respective roles of individual practitioners, health care institutions, and local, state, and federal governments. (To watch the symposium on-line, go to http://www.umaryland.edu/healthsecurity/related/Avian%20Flu%20Symposium%20Page). Having traveled to China during the Severe Acute Respiratory Syndrome (SARS) epidemic of 2002–2003 as part of a World Health Organization investigatory team, Dr. James Maguire provided first-hand knowledge of the potential challenges ahead. As head of the division of international health in Maryland’s department of epidemiology and preventive medicine, Maguire acknowledged that 8,000 cases of SARS may “seem trivial” in comparison to numbers projected for an avian flu pandemic, “But this was a close call. We heard a lot about China during the epidemic and most of it was criticism. But China also accomplished some amazing things.”

Recognizing that a third of SARS cases appeared among health care workers, Chinese officials adopted strict infection control measures, including patient isolation, restriction of visitors, the creation of 16 dedicated SARS hospitals, and the establishment of clear guidelines for case detection and surveillance. A massive public education campaign played an equally critical role in quashing what would surely have been a much wider spread of the disease.

The Chinese government’s central command enabled public health measures to be enacted with stunning speed and compliance. Health care workers were put on a 15-day quarantine. There were punishments for not reporting suspected cases. Schools and libraries were closed, and public events canceled. “A thousand-bed hospital was ordered to be built within a week,” said Maguire. “Huge amounts of supplies were ordered and distributed: gowns, masks, gloves, ambulances, ventilators. The infection-control measures were the heart of the success.”

Outdoor fever clinics were established, and check points set up that screened 14 million people for signs of infection. “If you had a fever, there really was nowhere to hide,” said Maguire. In short, he concluded, “China protected the rest of the world from SARS.”

Avian influenza is more readily transmissible than SARS, and most contagious prior to symptom onset. No drugs have been proven to work reliably against the disease. Vaccination and prevention may be our best hope, but officials are planning for the worst. Maryland’s medical center has established a broadly multidisciplinary emergency preparedness workgroup to tackle the myriad planning details required for true readiness.

By law, all Maryland hospitals have emergency preparedness plans, but not every hospital is equipped with a continuity of operations plan to ensure that the emergency plan will proceed smoothly in the event of massive workforce disruption. Dr. Julie Casani, director of public health preparedness and response at the Maryland Department of Health and Mental Hygiene puts the issue starkly: “What are you going to do when your CEO and CFO go down with the flu? Who’s signing the checks (for hospital workers)? Who’s making the emergency procurements? Who’s in charge?”

Hal Standiford, ’64, medical director for infection control and antimicrobial management at Maryland, described some of the steps already taken by the hospital. A cache of over 500 courses of Oseltamivir (Tamiflu) has been acquired at a cost of $30,000 to be used exclusively for treatment of infected patients and staff—not for prophylaxis. In addition, all hospital workers are being fit-tested for N95 air purifying respirators. These provide enhanced respiratory protection and are available in addition to the powered air purifying respirators. Infection control education is ongoing, and influenza guidelines have been established based on lessons from the SARS epidemic.

James Campbell, MD

Should an influenza pandemic strike, hospital doors would be locked and entry would be limited to the front entrance and the emergency room. Large triage tents would be set up along Penn Street for isolated screening of potential influenza patients. A separate treatment floor would be established with its own air unit for those known to have the disease, and another for those suspected to have it. (Currently there are twenty rooms in the hospital equipped for reverse isolation.) The medical and pediatric intensive care units would be reserved exclusively for patients with suspected influenza, with other patients transferred to different ICUs within the hospital or elsewhere.

Casani emphasizes the importance of engaging hospital staff in the planning process, keeping lines of communication open, and maintaining a genuine willingness to hear suggestions from everyone involved at every level. The practical needs could be overwhelming. “Maybe don’t count how many nurses do we need, but what nursing functions do we need, and who can do them?” says Casani. “Make sure that you’re not going to lose thirty percent of your workforce.”

While efforts are made to coordinate effective responses among health care institutions, the private medical sector, the wider community, and all levels of government, vaccine development continues to offer hope.

The NIH’s National Institute of Allergy and Infectious Disease has designated seven academic centers to serve as formal Vaccine Treatment and Evalu-ation Units (VTEUs). Since the inception of these competitive contracts in 1962, the medical school’s center for vaccine development (CVD) has earned VTEU status and maintained its position as a national leader in the area of vaccine development for diseases ranging from seasonal influenza to anthrax to smallpox. But no CVD study has received as much international media attention as the ongoing avian influenza vaccine trials, a contract worth approximately $20 million.

The first trial began in April, 2005, accepting 150 healthy adult volunteers between the ages of 18 and 64 to participate in a study comparing five injections: either a placebo, or one of four antigen doses: 7.5 mcg, 15 mcg, 45 mcg, or 90 mcg of hemagglutinin, one of the surface proteins found on the H5N1 virus. (Eleven percent of participants received placebo, the smallest number still capable of producing statistically reliable comparison.) The vaccine antigen was produced by Sanofi Pasteur in Swiftwater, Pennsylvania. A second trial enrolled people over age 65, and a third trial has commenced of children between the ages of two and nine. (Because teenagers tend to have similar side effects and immune responses as adults, this normally included demographic was skipped for the sake of expediency.)

Results from the initial trial have been analyzed, showing the vaccine to be safe, well tolerated, and likely protective at the higher doses. According to Campbell, “About half the people who got the 45 mcg or the 90 mcg had (antibody) responses after two doses that would make you think they’re in that protected level.” It wasn’t a slam dunk, but it showed clear benefit. “It’s about what we expected, actually. There have been previous avian flu trials, and this is what everyone has shown: it takes two doses, it takes higher doses. Even with that, you don’t get the same response that you get with human flu strains.”

Campbell talks with a reporter

Ideally, says Campbell, “you want a vaccine that’s true. If it protects only half, that’s not good enough. But it’s possible that the vaccine completely protects half and partially protects other people in that lower end. That may be okay from a public health point of view. Normally in a pandemic, let’s say 30–50% of the population is going to become infected, and we can cut that down to 15–25%—but of those 15–25%, instead of however many being hospitalized and dying, you cut that number down also (through partial protection). Then you really have a significant public health impact.”fs

Another trial is slated to test the vaccine with the addition of an adjuvant—aluminum hydroxide (alum)—which has been shown in some other vaccines to boost the immune response, yielding higher antibody levels than vaccine without alum. Campbell summarizes the results of the first trial as yielding “poor responses in the 7.5 and 15 mcg groups and modest responses in the higher. We would like to see great responses. We do not see great responses. That’s why we’re testing the alum.”

Media attention to avian flu has facilitated the recruitment of trial volunteers, who predominantly come from campus and the surrounding community. Where past vaccine trials have taken nine months to fill, the first avian flu trial enrolled all needed volunteers within five days. “People are afraid,” says Campbell. One volunteer, he recalls, used to mow lawns. “He was mowing a cemetery and later asked his parents why there were so many headstones with 1918 on them. They told him ‘That was the year of the pandemic. That’s the year your grandparents died.’ So he went back and found that his grandparents had both died in the Spanish Flu outbreak. That guy became an H5 volunteer.”