Review of Human Bird Flu Cases

There may be subtle differences in the disease caused by H5N1 viruses from different families or clades of viruses circulating in various parts of the world, a newly published scientific article suggests.

 The article, a review of data compiled on human cases to date, answers some questions about how the virus affects people. But it also makes clear that four years after the current wave of H5N1 infections began, many unsolved mysteries remain.

“I think in every area there are unanswered questions and one wants to see progress in every one of those areas, whether it's better understanding of transmission and what are the risk factors there and how often human-to-human transmission actually occurs,'' said senior author Dr. Frederick Hayden, a scientist with the World Health Organization's global influenza program.

The review article is based on data supplied by clinicians who have treated H5N1 and other research presented at a special WHO meeting held last March in Turkey. Hayden oversaw the project and led an international committee of experts who wrote the article, which appears in this week's New England Journal of Medicine. It reports that ongoing examination of the genetic structure of viruses shows they have evolved widely, currently breaking out into 10 separate families or clades.

Viruses from three of the clades are known to have caused human disease. Clade 2 viruses have broken into five subgroups, with 2.1 viruses endemic in Indonesia and 2.2 viruses spread through Russia, Europe, the Middle East and down into Northern Africa. Survival rates in certain countries are better than others, leading some to question whether the disease caused by some families of viruses is more severe than others. In Egypt, for instance, 44 per cent of cases have died; in Indonesia, 80 per cent of those infected have succumbed.

“There are some suggestions that there may be differences in some of the manifestations,'' Hayden said, but he noted there is still not enough evidence to say that with any certainty. That's because other factors could be at play. In Egypt, people infected with the virus have sought treatment more quickly, allowing for a more rapid start of antiviral drug therapy.

“Clearly time to treatment is a major variable  – antiviral treatment in particular – in terms of outcome,'' Hayden said.

The vagueness of the initial symptoms has contributed to the late start of antiviral drugs in many cases, which may be undermining the effectiveness of the therapy.

“It's a real challenge for clinicians,'' he said from Geneva. Antivirals like oseltamivir (Tamiflu) are supposed to be started within 48 hours of onset of symptoms for maximum efficacy.  Despite that, pooled evidence from cases in Thailand, Vietnam, Turkey, Egypt and Indonesia suggests that patients who get the drug are more likely to survive.

“I think that there is much better data now to support the conclusion that antiviral therapy does make a difference, even when it's sometime later in the course (of illness).

Although obviously mortality rates remain very high – unacceptably high,'' said Hayden, an expert in antiviral medications used for influenza. From late 2003 through Jan. 15 of this year, the WHO has confirmed 350 cases in 14 countries; 217 of those people have died. Most human cases have occurred among the young – 90 per cent of patients as of Dec. 24 were 40 years of age or younger. In fact, the median age of patients is about 18 years old. For reasons not yet understood, few older people have fallen ill with the disease.

The review noted that some research suggests that between 15 per cent and 20 per cent of older adults have some antibodies to the virus. But Hayden said it's unclear whether that's behind the small numbers of cases in older adults or whether older adults are less likely to do things – defeathering chickens, for instance – that might expose them to the virus. The variation in the way the disease attacks different age groups is also apparent in the death rate, which is highest among children aged 10 to 19 and lowest among people over age 50. The overall death rate among confirmed cases remains alarmingly high at 61 per cent. To date there have been six reported cases in pregnant women. Four have died and the two who survived suffered spontaneous abortions.

“It's a bad disease in any case but it seems particularly virulent in pregnancy,'' Hayden said.

The review reveals that there have been no confirmed cases of H5N1 illness among travellers to affected countries, but warns doctors seeing people with respiratory illnesses who've returned from these countries should consider it as a possible diagnosis. It also reveals that public health officials in the United States tested 41 returning ill passengers from 2003 to 2006, 27 of whom met the U.S. Centers for Disease Control's criteria for suspect H5N1 cases. None tested positive. The same test results were obtained for nearly 1,100 people in studies designed to look for missed cases of H5N1 infection.

Seven new studies from Cambodia, China, Thailand and Nigeria that looked for H5N1 antibodies in the blood of poultry cullers, live animal market workers, health-care workers and others who were in contact with H5N1 cases turned up only a single positive, in a live animal market worker in China.

Most diseases have a range of severity and experts had hoped the confirmed cases of H5N1 infection represented only the tip of a much larger iceberg. If that were true – if, say, there were 10 mild or virtually symptomless cases for every one found – that would dramatically lower the death rate. But these studies, when combined with earlier small studies that failed to find any real evidence mild infection was escaping detection, are compelling proof that this isn't the case at present with H5N1, Hayden said.

"I think it's persuasive that there was not (mild disease). Now it doesn't tell you what's going to happen in the future, of course. And that's why you need to keep looking,'' he said.

Clusters of two or more linked cases have been reported in 10 of the countries that have recorded human H5N1 infections. These clusters account for about a quarter of the total cases. Hayden said at present the WHO doesn't have a solid estimate of how many of these clusters involved suspected human-to-human spread of the virus, but an attempt to compile that figure is underway. More than 90 per cent of the clusters have occurred among blood-related family members – a fact that fuels ongoing debate over whether some people are genetically more vulnerable to the virus than others.