Three years into H5N1 outbreak, new research highlights how little is known

Three years into H5N1 outbreak, new research highlights how little is known
Published: Wednesday, November 22, 2006 | 8:14 PM ET
Canadian Press: HELEN BRANSWELL

(CP) - Three years into the outbreak of the H5N1 avian flu virus, two international teams of researchers scored major scientific credibility points Wednesday when the New England Journal of Medicine published their articles on the diagnosis and treatment of a mere 16 H5N1 patients.

With the official World Health Organization case count hovering near 260 human cases and 153 deaths from 10 countries, it might seem that the problems Turkish doctors experienced diagnosing eight patients in January or the investigation of three clusters of Indonesian patients last year wouldn't rate publication in the world's most prestigious medical journal.

But in fact, there is so little clinical and epidemiological information about H5N1 disease in the scientific literature that experts are eagerly welcoming the addition.

"Boy, it would just be nice to have more of this information out there," Dr. Keiji Fukuda, who heads the WHO's global influenza program, said in an interview from Geneva.

"It's tough. It's not easy getting this information."

A deputy editor of the journal agreed the information charting the virus in people is sparse.

"The number of documented human cases of H5N1 and the number of deaths attributed to it - well-characterized - is still a relatively small number," Dr. Lindsey Baden explained.

"We as a scientific and public health community need to have well-characterized the known human cases so that appropriate lessons can be learned."

Potential lessons from these papers include the observation by the Turkish researchers - from Yuzuncu Yil University in Van - that laboratories inexperienced with testing for H5N1 may have trouble confirming infections. They urged doctors in areas where there are H5N1 outbreaks in poultry to repeat sample taking and testing if initial tests come up negative for patients manifesting an H5N1-like disease.

The Indonesian paper points to the need to follow up with contacts of H5N1 patients. Three of the eight patients reported in the article experienced only mild disease and only came to light when investigators looked for illness in hospitalized cases.

The article noted limited human-to-human transmission may have occurred in two of the three clusters.

Both papers noted that diarrhea was rare among their H5N1 patients - a departure from the case description already in the medical literature. That may be due to the fact that the Turkish and Indonesian cases were caused by a different subgroup of viruses (called a clade) than cases outlined in earlier reports. But one of the authors of the Indonesia paper cautioned against drawing too many conclusions on too few patients.

"It would be interesting to look at clade 2 (infections) versus clade 1 (cases)," said Dr. Tim Uyeki of the U.S. Centers for Disease Control.

"But right now, it's not quite fair to do that. . . . There's a need for more epidemiological and clinical data on H5N1 patients."

The WHO is hoping to fill those knowledge gaps more efficiently in the future.

Scientists working with Fukuda are devising a checklist of basic information they hope attending doctors will collect for each future case of H5N1 infection - recording when people got sick, what symptoms they experienced, what their blood testing showed, which drugs they received and when, how patients responded, and which survived.

"Because there's no place that's having - fortunately - large numbers of cases, the only way to try to do this in a meaningful way is to collect as many of the cases from the different countries as possible," Dr. Frederick Hayden, a WHO scientist involved in the project, explained in a recent interview.

Collecting and sharing standardized information is the only way to start teasing out answers to the myriad questions that continue to puzzle scientists. With so many people exposed to this virus, why do so few get sick? Why do so many clusters of cases among blood relatives occur? Why do children make up such a disproportionate number of the total cases?

When considering the slow accumulation of H5N1 data, it's tempting to contrast it against the world's most recent emerging infectious disease experience - SARS.

But Dr. Malik Peiris - a leading SARS and influenza expert from the University of Hong Kong and an author of the Indonesian paper - cautioned that the analogy isn't a good one.

SARS exploded, triggering major outbreaks in places like Hong Kong, Taiwan, Hanoi and Toronto. The large volume of cases in teaching hospitals steeped in a tradition of research led to the rapid unravelling of an impressive number of SARS mysteries.

By comparison, H5N1 cases have occurred in random fashion in remote locales - villages in Cambodia, Indonesia, Vietnam, Azerbaijan, even war-torn Iraq.

"Here the cases are so dispersed," Peiris said. "There are so many clinicians involved, so many people involved, I think it makes it very difficult to pull these cases together from many different hospitals into one single analysis."

An infectious diseases expert not involved with the papers noted that it's not surprising so many questions remain about H5N1, given the enormous number of mysteries that remain unanswered about seasonal influenza.

"There are many, many questions with regard to influenza that have really only been recognized as important issues over the past 36 months," said Dr. Michael Osterholm, director of the University of Minnesota's Center for Infectious Diseases Research and Policy.

"We want to basically have this breadth of information (about H5N1) that's far and wide, and how do you do it when you're dealing with a disease that's only had 250-some cases documented from beginning to end right now?"

Even with a standardized form for data collection, accumulating information about the disease will remain challenging if cases continue to occur here and there in remote parts of the globe.

"Those very painstakingly developed studies and systems require people to come in - and that's a complete haphazard thing," Fukuda said.

© The Canadian Press, 2006